A common inversion under selection in Europeans

Heredity, 2008

In this study, we examine the frequency of a 900 kb inversion at 17q21.3 in the Gypsy and Caucasian populations of Hungary, which may reflect the Asian origin of Gypsy populations. Of the two haplotypes (H1 and H2), H2 is thought to be exclusively of Caucasian origin, and its occurrence in other racial groups is likely to reflect admixture. In our sample, the H1 haplotype was significantly more frequent in the Gypsy population (89.8 vs 75.5%, Po0.001) and was in Hardy-Weinberg disequilibrium (P ¼ 0.017). The 17q21.3 region includes the gene of microtubule-associated protein tau, and this result might imply higher sensitivity to H1 haplotype-related multifactorial tauopathies among Gypsies.

Nature Genetics, 2006

PLoS Genetics, 2014

Little is known about how changes in DNA methylation mediate risk for human diseases including dementia. Analysis of genome-wide methylation patterns in patients with two forms of tau-related dementia -progressive supranuclear palsy (PSP) and frontotemporal dementia (FTD) -revealed significant differentially methylated probes (DMPs) in patients versus unaffected controls. Remarkably, DMPs in PSP were clustered within the 17q21.31 region, previously known to harbor the major genetic risk factor for PSP. We identified and replicated a dose-dependent effect of the risk-associated H1 haplotype on methylation levels within the region in blood and brain. These data reveal that the H1 haplotype increases risk for tauopathy via differential methylation at that locus, indicating a mediating role for methylation in dementia pathophysiology.

Nature Genetics, 2009

Nature Biotechnology, 2011

Nature Genetics, 2011

Studies of recombination and how it varies depend crucially on accurate recombination maps. We propose a new approach for constructing high-resolution maps of relative recombination rates based on the observation of ancestry switch points among admixed individuals. We show the utility of this approach using simulations and by applying it to SNP genotype data from a sample of 2,565 African

BMC Neurology, 2009

The extended tau haplotype (H1) that covers the entire human microtubuleassociated protein tau (MAPT) gene has been implicated in Parkinson's disease (PD). Nevertheless, controversial results, such as two studies in Greek populations with opposite effects, have been reported. Therefore, we set out to determine whether the H1 haplotype and additional single nucleotide polymorphisms (SNPs) included in H1 are associated with PD in a sample of Greek patients.

American Journal of Human Genetics, 2007

Cytogenetic and Genome Research, 2006

imprinted gene(s) mapped to the chromosome region 15q11]q13. Four different mechanisms are known to cause the AS phenotype: 70% have a maternal deletion within 15q11]q13; 2-3% exhibit paternal uniparental disomy of chromosome 15 (UPD15); ϳ 2% have a mutation in the imprinting center and ϳ 8% have mutations in the UBE3A gene. Additionally, ϳ 15% of AS cases have an, as yet, undetected genetic mechanism. We report a patient with features reminiscent of AS, and a microdeletion detected by array-based comparative genomic hybridization (array-CGH).

Neurodegenerative Diseases, 2007

The frontotemporal lobar degenerations (FTLDs) are a group of disorders in which the clinical picture is not necessarily predictive of the underlying neuropathology. The FTLD with ubiquitin-only-immunoreactive neuronal changes (FTLD-U) subtype is pathologically characterized by ubiquitin-positive, tau and a-synuclein-negative neuronal cytoplasmic inclusions in the frontotemporal cortex and hippocampal dentate fascia. When similar pathological changes are accompanied by histological features of motor neuron disease (MND), the term FTLD-MND is used. The latter pathological changes may be found in patients with or without clinical evidence of MND. We retrospectively reviewed the clinical details of three patients with a rapidly progressive, levodopa-unresponsive bradykinetic-rigid syndrome and frontal cognitive impairment. A diagnosis of progressive supranuclear palsy (PSP) had been considered in all three cases at initial presentation. Two of the cases fulfilled clinical diagnostic criteria for PSP, which was the final clinical diagnosis during life. Pathological analysis showed typical histological appearances of FTLD-MND in two cases and of FTLD-U in one case. Semi-quantitative analysis of pathological load seemed to correlate with the clinical phenotype. FTLD-U or FTLD-MND should be considered in the differential diagnosis of progressive frontal dementia with an akinetic rigid syndrome and supranuclear gaze palsy or Steele-Richardson-Olszewski disease. Abbreviations: CAA = cerebral amyloid angiopathy; CBD = corticobasal degeneration; DUI = dementia with tau-negative ubiquitin-positive inclusions; EMG = electromyography; FTD = frontotemporal dementia; FTLD = frontotemporal lobar degeneration; FTLD-U = FTLD with ubiquitin-only-immunoreactive neuronal changes; FTLD-MND = FTLD with motor neuron disease; FTDP-17 = frontotemporal dementia with parkinsonism linked to chromosome 17; ITSNU = inclusions, tau and asynuclein-negative, ubiquitinated; MMSE = mini-mental state examination; MND = motor neuron disease; MND-ID = motor neuron disease inclusion body dementia; NINDS-SPSP = National Institute of Neurological Disorders and Stroke-Society for Progressive Supranuclear Palsy; OKN = optokinetic nystagmus; PNFA = progressive non-fluent aphasia; PSP = progressive supranuclear palsy; riMLF = rostral interstitial nucleus of the medial longitudinal fascicle; SD = semantic dementia; WAIS-R = revised Weschler adult intelligence scale

Nature Genetics, 2014

Osteoarthritis is the most common form of arthritis and is a major cause of pain and disability in the elderly. To search for sequence variants that confer risk of osteoarthritis of the hand, we carried out a genome-wide association study (GWAS) in subjects with severe hand osteoarthritis, using variants identified through the whole-genome sequencing of 2,230 Icelanders. We found two significantly associated loci in the Icelandic discovery set: at 15q22 (frequency of 50.7%, odds ratio (OR) = 1.51, P = 3.99 × 10 −10 ) in the ALDH1A2 gene and at 1p31 (frequency of 0.02%, OR = 50.6, P = 9.8 × 10 −10 ). Among the carriers of the variant at 1p31 is a family with several members in whom the risk allele segregates with osteoarthritis. The variants within the ALDH1A2 gene were confirmed in replication sets from The Netherlands and the UK, yielding an overall association of OR = 1.46 and P = 1.1 × 10 −11 (rs3204689).

American Journal of Human Genetics, 2007

To date, only the H1 MAPT haplotype has been consistently associated with risk of developing the neurodegenerative disease progressive supranuclear palsy (PSP). We hypothesized that additional genetic loci may be involved in conferring risk of PSP that could be identified through a pooling-based genomewide association study of 1500,000 SNPs. Candidate SNPs with large differences in allelic frequency were identified by ranking all SNPs by their probe-intensity difference between cohorts. The MAPT H1 haplotype was strongly detected by this methodology, as was a second major locus on chromosome 11p12-p11 that showed evidence of association at allelic ( ), genotypic ( ), and haplotypic P ! .001 P ! .001 ( ) levels and was narrowed to a single haplotype block containing the DNA damage-binding protein 2 (DDB2) P ! .001 and lysosomal acid phosphatase 2 (ACP2) genes. Since DNA damage and lysosomal dysfunction have been implicated in aging and neurodegenerative processes, both genes are viable candidates for conferring risk of disease. From the Departments of Neuroscience (S.M.; R.C.; M.B.; J.G.; J.A.; A.C.; S.L.; M.J.F.; D.W.D.; M.H.) and Neurology (R.J.U.; Z.K.W.; N.(D.W.C.; M.J.H.; J.V.P.; V.L.Z.; S.S.; J.C.; K.D.C.; D.A.S.);

Human Mutation, 2013

We delineated the genome-wide distribution of IP-LCRs >1 kB in size with >95% sequence identity and mapped the genes, potentially intersected by an inversion, that overlap at least one of the IP-LCRs. Remarkably, our results show that 12.0% of the human genome is potentially susceptible to such inversions and 942 genes, 99 of which are on the X chromosome, are predicted to be disrupted secondary to such an inversion! In addition, IP-LCRs larger than 800 bp with at least 98% sequence identity (duplication/triplication facilitating IP-LCRs, DTIP-LCRs) were recently implicated in the formation of complex genomic rearrangements with a duplicationinverted triplication-duplication (DUP-TRP/INV-DUP) structure by a replication-based mechanism involving a template switch between such inverted repeats. We identified 1,551 DTIP-LCRs that could facilitate DUP-TRP/INV-DUP formation. Remarkably, 1,445 diseaseassociated genes are at risk of undergoing copy-number gain as they map to genomic intervals susceptible to the formation of DUP-TRP/INV-DUP complex rearrangements. We implicate inverted LCRs as a human genome architectural feature that could potentially be responsi-

Nature Genetics, 2010

Previously, we reported germline DNA variants associated with risk of urinary bladder cancer (UBC) in Dutch and Icelandic subjects. Here we expanded the Icelandic sample set and tested the top 20 markers from the combined analysis in several European case-control sample sets, with a total of 4,739 cases and 45,549 controls. The T allele of rs798766 on 4p16.3 was found to associate with UBC (odds ratio = 1.24, P = 9.9 × 10 −12 ). rs798766 is located in an intron of TACC3, 70 kb from FGFR3, which often harbors activating somatic mutations in low-grade, noninvasive UBC. Notably, rs798766[T] shows stronger association with low-grade and low-stage UBC than with more aggressive forms of the disease and is associated with higher risk of recurrence in low-grade stage Ta tumors.

PLoS Genetics, 2013

BRCA1-associated breast and ovarian cancer risks can be modified by common genetic variants. To identify further cancer risk-modifying loci, we performed a multi-stage GWAS of 11,705 BRCA1 carriers (of whom 5,920 were diagnosed with breast and 1,839 were diagnosed with ovarian cancer), with a further replication in an additional sample of 2,646 BRCA1 carriers. We identified a novel breast cancer risk modifier locus at 1q32 for BRCA1 carriers (rs2290854, P = 2.7610 28 , HR = 1.14, 95% CI: 1.09-1.20). In addition, we identified two novel ovarian cancer risk modifier loci: 17q21.31 (rs17631303, P = 1.4610 28 , HR = 1.27, 95% CI: 1.17-1.38) and 4q32.3 (rs4691139, P = 3.4610 28 , HR = 1.20, 95% CI: 1.17-1.38). The 4q32.3 locus was not associated with ovarian cancer risk in the general population or BRCA2 carriers, suggesting a BRCA1-specific association. The 17q21.31 locus was also associated with ovarian cancer risk in 8,211 BRCA2 carriers (P = 2610 24 ). These loci may lead to an improved understanding of the etiology of breast and ovarian tumors in BRCA1 carriers. Based on the joint distribution of the known BRCA1 breast cancer risk-modifying loci, we estimated that the breast cancer lifetime risks for the 5% of BRCA1 carriers at lowest risk are 28%-50% compared to 81%-100% for the 5% at highest risk. Similarly, based on the known ovarian cancer risk-modifying loci, the 5% of BRCA1 carriers at lowest risk have an estimated lifetime risk of developing ovarian cancer of 28% or lower, whereas the 5% at highest risk will have a risk of 63% or higher. Such differences in risk may have important implications for risk prediction and clinical management for BRCA1 carriers.

PLoS Genetics, 2014

In recent years different types of structural variants (SVs) have been discovered in the human genome and their functional impact has become increasingly clear. Inversions, however, are poorly characterized and more difficult to study, especially those mediated by inverted repeats or segmental duplications. Here, we describe the results of a simple and fast inverse PCR (iPCR) protocol for high-throughput genotyping of a wide variety of inversions using a small amount of DNA. In particular, we analyzed 22 inversions predicted in humans ranging from 5.1 kb to 226 kb and mediated by inverted repeat sequences of 1.6-24 kb. First, we validated 17 of the 22 inversions in a panel of nine HapMap individuals from different populations, and we genotyped them in 68 additional individuals of European origin, with correct genetic transmission in ,12 mother-father-child trios. Global inversion minor allele frequency varied between 1% and 49% and inversion genotypes were consistent with Hardy-Weinberg equilibrium. By analyzing the nucleotide variation and the haplotypes in these regions, we found that only four inversions have linked tag-SNPs and that in many cases there are multiple shared SNPs between standard and inverted chromosomes, suggesting an unexpected high degree of inversion recurrence during human evolution. iPCR was also used to check 16 of these inversions in four chimpanzees and two gorillas, and 10 showed both orientations either within or between species, providing additional support for their multiple origin. Finally, we have identified several inversions that include genes in the inverted or breakpoint regions, and at least one disrupts a potential coding gene. Thus, these results represent a significant advance in our understanding of inversion polymorphism in human populations and challenge the common view of a single origin of inversions, with important implications for inversion analysis in SNP-based studies.

Nature Genetics, 2008

Using comparative sequencing approaches, we investigated the evolutionary history of the Europeanenriched 17q21.31 MAPT inversion polymorphism. We present a detailed, BAC-based sequence assembly of the inverted human H2 haplotype and contrast it with the sequence structure and genetic variation of the corresponding 1.5 Mb region for the non-inverted H1 human haplotype and that of chimpanzee and orangutan. We find that inversion of the MAPT region is similarly polymorphic in other great ape species and present evidence that the inversions have occurred independently in both chimpanzee and humans. In humans, the inversion breakpoints correspond to core duplications encoding the LRRC37 gene family. Our analysis favors the H2 configuration and sequence haplotype as the likely great ape/human ancestral state with inversion recurrences during primate evolution. We demonstrate that the H2 architecture has evolved more extensive sequence homology, perhaps explaining its preference to undergo microdeletion associated with mental retardation in European populations. †Correspondence to

Annals of Human Genetics, 2012

Studies of the genomic structure of the Greek population and Southeastern Europe are limited, despite the central position of the area as a gateway for human migrations into Europe. HapMap has provided a unique tool for the analysis of human genetic variation. Europe is represented by the CEU (Northwestern Europe) and the TSI populations (Tuscan Italians from Southern Europe), which serve as reference for the design of genetic association studies. Furthermore, genetic association findings are often transferred to unstudied populations. Although initial studies support the fact that the CEU can, in general, be used as reference for the selection of tagging SNPs in European populations, this has not been extensively studied across Europe. We set out to explore the genomic structure of the Greek population (56 individuals) and compare it to the HapMap TSI and CEU populations. We studied 1112 SNPs (27 regions, 13 chromosomes). Although the HapMap European populations are, in general, a good reference for the Greek population, regions of population differentiation do exist and results should not be light-heartedly generalized. We conclude that, perhaps due to the individual evolutionary history of each genomic region, geographic proximity is not always a perfect guide for selecting a reference population for an unstudied population.

Human Mutation, 2012

Nonallelic homologous recombination (NAHR) is the major mechanism underlying recurrent genomic rearrangements, including the large deletions at 17q11.2 that cause neurofibromatosis type 1 (NF1). Here, we identify a novel NAHR hotspot, responsible for type-3 NF1 deletions that span 1.0 Mb. Breakpoint clustering within this 1-kb hotspot, termed PRS3, was noted in 10 of 11 known type-3 NF1 deletions. PRS3 is located within the LRRC37B pseudogene of the NF1-REPb and NF1-REPc low-copy repeats. In contrast to other previously characterized NAHR hotspots, PRS3 has not developed on a preexisting allelic homologous recombination hotspot. Furthermore, the variation pattern of PRS3 and its flanking regions is unusual since only NF1-REPc (and not NF1-REPb) is characterized by a high single nucleotide polymorphism (SNP) frequency, suggestive of unidirectional sequence transfer via nonallelic homologous gene conversion (NAHGC). By contrast, the previously described intense NAHR hotspots within the CMT1A-REPs, and the PRS1 and PRS2 hotspots underlying type-1 NF1 deletions, experience frequent bidirectional sequence transfer. PRS3 within NF1-REPc was also found to be involved in NAHGC with the LRRC37B gene, the progenitor locus of the LRRC37B-P duplicons, as indicated by the presence of shared SNPs between these loci. PRS3 therefore represents a weak (and probably evolutionarily rather young) NAHR hotspot with unique properties.

Nature, 2015

Nature genetics, 2007

We conducted a genome-wide association study for type 2 diabetes (T2D) in Icelandic cases and controls, and we found that a previously described variant in the transcription factor 7-like 2 gene (TCF7L2) gene conferred the most significant risk. In addition to confirming two recently identified risk variants, we identified a variant in the CDKAL1 gene that was associated with T2D in individuals of European ancestry (allele-specific odds ratio (OR) = 1.20 (95% confidence interval, 1.13-1.27), P = 7.7 x 10(-9)) and individuals from Hong Kong of Han Chinese ancestry (OR = 1.25 (1.11-1.40), P = 0.00018). The genotype OR of this variant suggested that the effect was substantially stronger in homozygous carriers than in heterozygous carriers. The ORs for homozygotes were 1.50 (1.31-1.72) and 1.55 (1.23-1.95) in the European and Hong Kong groups, respectively. The insulin response for homozygotes was approximately 20% lower than for heterozygotes or noncarriers, suggesting that this varian...

Science, 2010

PLoS Genetics, 2009

Variation in genes underlying host immunity can lead to marked differences in susceptibility to HIV infection among humans. Despite heavy reliance on non-human primates as models for HIV/AIDS, little is known about which host factors are shared and which are unique to a given primate lineage. Here, we investigate whether copy number variation (CNV) at CCL3-like genes (CCL3L), a key genetic host factor for HIV/AIDS susceptibility and cell-mediated immune response in humans, is also a determinant of time until onset of simian-AIDS in rhesus macaques. Using a retrospective study of 57 rhesus macaques experimentally infected with SIVmac, we find that CCL3L CNV explains approximately 18% of the variance in time to simian-AIDS (p,0.001) with lower CCL3L copy number associating with more rapid disease course. We also find that CCL3L copy number varies significantly (p,10 26 ) among rhesus subpopulations, with Indian-origin macaques having, on average, half as many CCL3L gene copies as Chinese-origin macaques. Lastly, we confirm that CCL3L shows variable copy number in humans and chimpanzees and report on CCL3L CNV within and among three additional primate species. On the basis of our findings we suggest that (1) the difference in population level copy number may explain previously reported observations of longer post-infection survivorship of Chinese-origin rhesus macaques, (2) stratification by CCL3L copy number in rhesus SIV vaccine trials will increase power and reduce noise due to non-vaccine-related differences in survival, and (3) CCL3L CNV is an ancestral component of the primate immune response and, therefore, copy number variation has not been driven by HIV or SIV per se.

Nature, 2006

Chromosome 17 is unusual among the human chromosomes in many respects. It is the largest human autosome with orthology to only a single mouse chromosome, mapping entirely to the distal half of mouse chromosome 11. Chromosome 17 is rich in protein-coding genes, having the second highest gene density in the genome. It is also enriched in segmental duplications, ranking third in density among the autosomes. Here we report a finished sequence for human chromosome 17, as well as a structural comparison with the finished sequence for mouse chromosome 11, the first finished mouse chromosome. Comparison of the orthologous regions reveals striking differences. In contrast to the typical pattern seen in mammalian evolution, the human sequence has undergone extensive intrachromosomal rearrangement, whereas the mouse sequence has been remarkably stable. Moreover, although the human sequence has a high density of segmental duplication, the mouse sequence has a very low density. Notably, these segmental duplications correspond closely to the sites of structural rearrangement, demonstrating a link between duplication and rearrangement. Examination of the main classes of duplicated segments provides insight into the dynamics underlying expansion of chromosome-specific, low-copy repeats in the human genome.

The Pharmacogenomics Journal, 2013

Inhaled corticosteroids are the most commonly used controller medications prescribed for asthma. Two single-nucleotide polymorphisms (SNPs), rs1876828 in CRHR1 and rs37973 in GLCCI1, have previously been associated with corticosteroid efficacy. We studied data from four existing clinical trials of asthmatics who received inhaled corticosteroids and had lung function measured by forced expiratory volume in one second (FEV1) before and after the period of such treatment. We combined the two SNPs rs37973 and rs1876828 into a predictive test of FEV1 change using a Bayesian model, which identified patients with good or poor steroid response (highest or lowest quartile, respectively) with predictive performance of 65.7% (p = 0.039 vs. random) area under the receiver-operator characteristic curve in the training population and 65.9% (p = 0.025 vs. random) in the test population. These findings show that two genetic variants can be combined into a predictive test that achieves similar accuracy and superior replicability compared with single SNP predictors.

PLoS ONE, 2010

Background: The high frequency (around 0.70 worlwide) and the relatively young age (between 14,000 and 62,000 years) of a derived group of haplotypes, haplogroup D, at the microcephalin (MCPH1) locus led to the proposal that haplogroup D originated in a human lineage that separated from modern humans .1 million years ago, evolved under strong positive selection, and passed into the human gene pool by an episode of admixture circa 37,000 years ago. The geographic distribution of haplogroup D, with marked differences between Africa and Eurasia, suggested that the archaic human form admixing with anatomically modern humans might have been Neanderthal.

Nature Genetics, 2011

Progressive supranuclear palsy (PSP) is a movement disorder with prominent tau neuropathology. Brain diseases with abnormal tau deposits are called tauopathies, the most common of which is Alzheimer's disease. Environmental causes of tauopathies include repetitive head trauma associated with some sports. To identify common genetic variation contributing to risk for tauopathies, we carried out a genome-wide association study of 1,114 individuals with PSP (cases) and 3,247 controls (stage 1) followed by a second stage in which we genotyped 1,051 cases and 3,560 controls for the stage 1 SNPs that yielded P ≤ 10(-3). We found significant previously unidentified signals (P < 5 × 10(-8)) associated with PSP risk at STX6, EIF2AK3 and MOBP. We confirmed two independent variants in MAPT affecting risk for PSP, one of which influences MAPT brain expression. The genes implicated encode proteins for vesicle-membrane fusion at the Golgi-endosomal interface, for the endoplasmic reticulum unfolded protein response and for a myelin structural component.

Human Mutation, 2006

We experimentally investigated more than 1,200 entries in dbSNP that would change amino-acids (nsSNPs), using various subsets of DNA samples drawn from 18 global populations (1,000 subjects in total). First, we mined the data for any SNP features that correlated with a high validation rate. Useful predictors of valid SNPs included multiple submissions to dbSNP, having a dbSNP validation statement, and being present in a low number of ESTs. Together, these features improved validation rates by almost 10-fold. Higher-abundance SNPs (e.g., T/C variants) also validated more frequently. Second, we considered derived alleles and noted a considerably (10%) increased average derived allele frequency (DAF) in Europeans vs. Africans, plus a further increase in some other populations. This was not primarily due to an SNP ascertainment bias, nor to the effects of natural selection. Instead, it can be explained as a drift-based, progressive increase in DAF that occurs over many generations and becomes exaggerated during population bottlenecks. This observation could be used as the basis for novel DAF-based tests for comparing demographic histories. Finally, we considered individual marker patterns and identified 37 SNPs with allele frequency variance or F ST values consistent with the effects of population-specific natural selection. Four particularly striking clusters of these markers were apparent, and three of these coincide with genes/regions from among only several dozen such domains previously suggested by others to carry signatures of selection. Hum Mutat 27(2), 173-186, 2006. r r 2006 Wiley-Liss, Inc.

BMC genetics, 2007

Late onset Alzheimer's disease (LOAD) is a common sporadic form of the illness, affecting individuals above the age of 65 yrs. A prominent hypothesis for the aetiopathology of Alzheimer's disease is that in the presence of a beta-amyloid load, individuals expressing a pathogenic form of tau protein (MAPT) are at increased risk for developing the disease. Genetic studies in this pursuit have, however, yielded conflicting results. A recent study showed a significant haplotype association (H1c) with AD. The current study is an attempt to replicate this association in an independently ascertained cohort. In this report we present the findings of a haplotype analysis at the MAPT locus. We failed to detect evidence of association of the H1c haplotype at the MAPT locus with LOAD. None of the six SNPs forming the H1c haplotype showed evidence of association with disease. In addition, nested clade analysis suggested the presence of independent mutations at multiple points in the hapl...

Nature Genetics, 2006

PLOS Genetics, 2015

Despite many years of study into inversions, very little is known about their functional consequences, especially in humans. A common hypothesis is that the selective value of inversions stems in part from their effects on nearby genes, although evidence of this in natural populations is almost nonexistent. Here we present a global analysis of a new 415-kb polymorphic inversion that is among the longest ones found in humans and is the first with clear position effects. This inversion is located in chromosome 19 and has been generated by non-homologous end joining between blocks of transposable elements with low identity. PCR genotyping in 541 individuals from eight different human populations allowed the detection of tag SNPs and inversion genotyping in multiple populations worldwide, showing that the inverted allele is mainly found in East Asia with an average frequency of 4.7%. Interestingly, one of the breakpoints disrupts the transcription factor gene ZNF257, causing a significant reduction in the total expression level of this gene in lymphoblastoid cell lines. RNA-Seq analysis of the effects of this expression change in standard homozygotes and inversion heterozygotes revealed distinct expression patterns that were validated by quantitative RT-PCR. Moreover, we have found a new fusion transcript that is generated exclusively from inverted chromosomes around one of the breakpoints. Finally, by the analysis of the associated nucleotide variation, we have estimated that the inversion was generated 40,000-50,000 years ago and, while a neutral evolution cannot be ruled out, its current frequencies are more consistent with those expected for a deleterious variant, although no significant association with phenotypic traits has been found so far.

European Journal of Human Genetics, 2015

The Koolen-de Vries syndrome (KdVS; OMIM #610443), also known as the 17q21.31 microdeletion syndrome, is a clinically heterogeneous disorder characterised by (neonatal) hypotonia, developmental delay, moderate intellectual disability, and characteristic facial dysmorphism. Expressive language development is particularly impaired compared with receptive language or motor skills. Other frequently reported features include social and friendly behaviour, epilepsy, musculoskeletal anomalies, congenital heart defects, urogenital malformations, and ectodermal anomalies. The syndrome is caused by a truncating variant in the KAT8 regulatory NSL complex unit 1 (KANSL1) gene or by a 17q21.31 microdeletion encompassing KANSL1. Herein we describe a novel cohort of 45 individuals with KdVS of whom 33 have a 17q21.31 microdeletion and 12 a single-nucleotide variant (SNV) in KANSL1 (19 males, 26 females; age range 7 months to 50 years). We provide guidance about the potential pitfalls in the laboratory testing and emphasise the challenges of KANSL1 variant calling and DNA copy number analysis in the complex 17q21.31 region. Moreover, we present detailed phenotypic information, including neuropsychological features, that contribute to the broad phenotypic spectrum of the syndrome. Comparison of the phenotype of both the microdeletion and SNV patients does not show differences of clinical importance, stressing that haploinsufficiency of KANSL1 is sufficient to cause the full KdVS phenotype.

European Journal of Neurology, 2010

Background and purpose: Whilst an association between the tau gene (MAPT)-containing H1 haplotype and supranuclear gaze palsy (PSP) has long been recognized, the effect of H1 on risk for ParkinsonÕs disease (PD) has remained more contentious. Methods: Herein, we examined the association of H1 and PD in three Caucasian PD patient-control series from Ireland, Norway, and the US (combined: n = 2619), by genotyping two H1/H2 single nucleotide polymorphisms (SNPs) in MAPT (rs1052553) and in the Saitohin gene (rs62063857) and one H1-specific SNP (rs242557). Results: We identified a significant association between H1/H2 and risk of PD (rs1052553 OR: 1.43, CI: 1.23-1.64; rs62063857 OR: 1.45, CI: 1.27-1.67), but no effect of the H1-specific SNP rs242557 (OR: 0.92, CI: 0.82-1.03). Conclusions: Our findings show that the H1 haplotype is a significant risk factor for PD. However, one H1-specific SNP (rs242557) previously implicated in PSP did not alter the risk of PD, indicating that distinct H1 sub-haplotypes probably drive the associations with PD and PSP.

Nature, 2015

Structural variants are implicated in numerous diseases and make up the majority of varying nucleotides among human genomes. Here we describe an integrated set of eight structural variant classes comprising both balanced and unbalanced variants, which we constructed using short-read DNA sequencing data and statistically phased onto haplotype blocks in 26 human populations. Analysing this set, we identify numerous gene-intersecting structural variants exhibiting population stratification and describe naturally occurring homozygous gene knockouts that suggest the dispensability of a variety of human genes. We demonstrate that structural variants are enriched on haplotypes identified by genome-wide association studies and exhibit enrichment for expression quantitative trait loci. Additionally, we uncover appreciable levels of structural variant complexity at different scales, including genic loci subject to clusters of repeated rearrangement and complex structural variants with multipl...

Nature Genetics, 2005

Nature Genetics, 2006

Nature Communications, 2013

Chromosomal rearrangements are mutations contributing to both within and between species variation; however their contribution to fitness is yet to be measured. Here we show that chromosomal rearrangements are pervasive in natural isolates of Schizosaccharomyces pombe and contribute to reproductive isolation. To determine the fitness effects of chromosome structure, we constructed two inversions and eight translocations without changing the coding sequence. We show that chromosomal rearrangements contribute to both reproductive success in meiosis and growth rate in mitosis with a strong genotype by environment interaction. These changes are accompanied by alterations in gene expression. Strikingly, we find several examples leading to antagonistic pleiotropy. Even though chromosomal rearrangements may have a deleterious effect during sexual reproduction, some compensate with a strong growth advantage in mitosis. Our results constitute the first quantification of fitness effects caused by de novo mutations that result in chromosomal rearrangement variation and suggest a mechanism for their maintenance in natural populations.

Science, 2007

Structural variation of the genome involves kilobase-to megabase-sized deletions, duplications, insertions, inversions, and complex combinations of rearrangements. We introduce highthroughput and massive paired-end mapping (PEM), a large-scale genome-sequencing method to identify structural variants (SVs) ~3 kilobases (kb) or larger that combines the rescue and capture of paired ends of 3-kb fragments, massive 454 sequencing, and a computational approach to map DNA reads onto a reference genome. PEM was used to map SVs in an African and in a putatively European individual and identified shared and divergent SVs relative to the reference genome. Overall, we fine-mapped more than 1000 SVs and documented that the number of SVs among humans is much larger than initially hypothesized; many of the SVs potentially affect gene function. The breakpoint junction sequences of more than 200 SVs were determined with a novel pooling strategy and computational analysis. Our analysis provided insights into the mechanisms of SV formation in humans.

PLoS genetics, 2012

Androgenetic alopecia (AGA) is a highly heritable condition and the most common form of hair loss in humans. Susceptibility loci have been described on the X chromosome and chromosome 20, but these loci explain a minority of its heritable variance. We conducted a large-scale meta-analysis of seven genome-wide association studies for early-onset AGA in 12,806 individuals of European ancestry. While replicating the two AGA loci on the X chromosome and chromosome 20, six novel susceptibility loci reached genome-wide significance (p = 2.62×10(-9)-1.01×10(-12)). Unexpectedly, we identified a risk allele at 17q21.31 that was recently associated with Parkinson's disease (PD) at a genome-wide significant level. We then tested the association between early-onset AGA and the risk of PD in a cross-sectional analysis of 568 PD cases and 7,664 controls. Early-onset AGA cases had significantly increased odds of subsequent PD (OR = 1.28, 95% confidence interval: 1.06-1.55, p = 8.9×10(-3)). Fu...

The American Journal of Human Genetics, 2006

The coding regions of many of the major histocompatibility complex (MHC) (human leukocyte antigen [HLA] in humans) molecules are believed to be subject to balancing selection. But it is less certain whether the regulatory regions of such coding sequences are also subject to the same type of selection. Here, we studied the polymorphism of the regulatory regions of the HLA-DPA1 and HLA-DPB1 genes among ethnic minorities in southwestern China. Phylogenetic analysis revealed two deep clades 110 million years old. There is almost complete linkage disequilibrium between the regulatory and coding regions of HLA-DPA1, which hints at coadaptive balancing selection on the entire region. Thus, the molecular mechanism of balancing selection in MHC may involve expression modulation in addition to coding-region polymorphisms. Although the frequency of clade II is 130% in some ethnic minorities, it decreases to !5% among southern Han Chinese and vanishes among Europeans. As suspected, some ancient balanced polymorphisms, lost in major populations, still exist in isolated ethnicities. These isolated populations may thus contribute disproportionately to the total diversity of modern humans.

The American Journal of Human Genetics, 2006

We report the clinical characteristics of a schizophrenia sample of 409 pedigrees-263 of European ancestry (EA) and 146 of African American ancestry (AA)-together with the results of a genome scan (with a simple tandem repeat polymorphism interval of 9 cM) and follow-up fine mapping. A family was required to have a proband with schizophrenia (SZ) and one or more siblings of the proband with SZ or schizoaffective disorder. Linkage analyses included 403 independent full-sibling affected sibling pairs (ASPs) (279 EA and 124 AA) and 100 allpossible half-sibling ASPs (15 EA and 85 AA). Nonparametric multipoint linkage analysis of all families detected two regions with suggestive evidence of linkage at 8p23.3-q12 and 11p11.2-q22.3 (empirical Z likelihood-ratio score [Z lr ] threshold у2.65) and, in exploratory analyses, two other regions at 4p16.1-p15.32 in AA families and at 5p14.3-q11.2 in EA families. The most significant linkage peak was in chromosome 8p; its signal was mainly driven by the EA families. Z lr scores 12.0 in 8p were observed from 30.7 cM to 61.7 cM (Center for Inherited Disease Research map locations). The maximum evidence in the full sample was a multipoint Z lr of 3.25 (equivalent Kong-Cox LOD of 2.30) near D8S1771 (at 52 cM); there appeared to be two peaks, both telomeric to neuregulin 1 (NRG1). There is a paracentric inversion common in EA individuals within this region, the effect of which on the linkage evidence remains unknown in this and in other previously analyzed samples. Fine mapping of 8p did not significantly alter the significance or length of the peak. We also performed fine mapping of 4p16.3-p15.2, 5p15. 3. The highest increase in Z lr scores was observed for 5p14.1-q12.1, where the maximum Z lr increased from 2.77 initially to 3.80 after fine mapping in the EA families.

Journal of Evolutionary Biology, 2017

Polymorphic inversions are ubiquitous across the animal kingdom and are frequently associated with clines in inversion frequencies across environmental gradients. Such clines are thought to result from selection favouring local adaptation; however, empirical tests are scarce. The seaweed fly Coelopa frigida has an a/b inversion polymorphism, and previous work demonstrated that the a inversion frequency declines from the North Sea to the Baltic Sea and is correlated with changes in tidal range, salinity, algal composition and wrackbed stability. Here, we explicitly test the hypothesis that populations of C. frigida along this cline are locally adapted by conducting a reciprocal transplant experiment of four populations along this cline to quantify survival. We found that survival varied significantly across treatments and detected a significant Location x Substrate interaction, indicating local adaptation. Survival models showed that flies from locations at both extremes had highest survival on their native substrates, demonstrating that local adaptation is present at the extremes of the cline. Survival at the two intermediate locations was, however, not elevated at the native substrates, suggesting that gene flow in intermediate habitats may override selection. Together, our results support the notion that population extremes of species with polymorphic inversions are often locally adapted, even when spatially close, consistent with the growing view that inversions can have direct and strong effects on the fitness of species.

BMC genomics, 2017

Although many algorithms are now available that aim to characterize different classes of structural variation, discovery of balanced rearrangements such as inversions remains an open problem. This is mainly due to the fact that breakpoints of such events typically lie within segmental duplications or common repeats, which reduces the mappability of short reads. The algorithms developed within the 1000 Genomes Project to identify inversions are limited to relatively short inversions, and there are currently no available algorithms to discover large inversions using high throughput sequencing technologies. Here we propose a novel algorithm, VALOR, to discover large inversions using new sequencing methods that provide long range information such as 10X Genomics linked-read sequencing, pooled clone sequencing, or other similar technologies that we commonly refer to as long range sequencing. We demonstrate the utility of VALOR using both pooled clone sequencing and 10X Genomics linked-re...

Heredity, 2017

We examined tau haplotype frequencies in two different ethnical groups from the Basque Country (BC): Roma people and residents of European ancestry (general population). In addition, we analyzed the spatial distribution of tau haplotypes in Eurasian populations to explore the genetic affinities of the Romani groups living in Europe in a broader scope. The 17q21.31 genomic region was characterized through the genotyping of two diagnostic single nucleotide polymorphisms, SNPs (rs10514879 and rs199451), which allow the identification of H1 and H2 haplotypes. A significant heterozygous deficit was detected in the Romani for rs10514879. The H2 haplotype frequency proved to be more than twice in the BC general population (0.283) than in the Roma people (0.127). In contrast, H2 frequency proved to be very similar between Basque and Hungarian Romani, and similar to the H2 frequencies found in northwestern India and Pakistan as well. Several statistical analyses unveiled genetic structuring ...

Proceedings of the National Academy of Sciences

Inversion polymorphisms in the African malaria vector Anopheles gambiae segregate along climatic gradients of aridity. Despite indirect evidence of their adaptive significance, little is known of the phenotypic targets of selection or the underlying genetic mechanisms. Here we adopt a systems genetics approach to explore the interaction of two inversions on opposite arms of chromosome 2 with gender, climatic conditions, and one another. We measure organismal traits and transcriptional profiles in 8-d-old adults of both sexes and four alternative homokaryotypic classes reared under two alternative climatic regimes. We show that karyotype strongly influences both organismal traits and transcriptional profiles but that the strength and direction of the effects depend upon complex interactions with gender and environmental conditions and between inversions on independent arms. Our data support the suppressed recombination model for the role of inversions in local adaptation, and—support...

PLoS Genetics, 2011

In humans, chromosome-number abnormalities have been associated with altered recombination and increased maternal age. Therefore, age-related effects on recombination are of major importance, especially in relation to the mechanisms involved in human trisomies. Here, we examine the relationship between maternal age and recombination rate in humans. We localized crossovers at high resolution by using over 600,000 markers genotyped in a panel of 69 French-Canadian pedigrees, revealing recombination events in 195 maternal meioses. Overall, we observed the general patterns of variation in fine-scale recombination rates previously reported in humans. However, we make the first observation of a significant decrease in recombination rates with advancing maternal age in humans, likely driven by chromosome-specific effects. The effect appears to be localized in the middle section of chromosomal arms and near subtelomeric regions. We postulate that, for some chromosomes, protection against non-disjunction provided by recombination becomes less efficient with advancing maternal age, which can be partly responsible for the higher rates of aneuploidy in older women. We propose a model that reconciles our findings with reported associations between maternal age and recombination in cases of trisomies.

Scientific Reports

Cytological and molecular studies have revealed that inversion chromosomal polymorphism is widespread across taxa and that inversions are among the most common structural changes fixed between species. Two major mechanisms have been proposed for the origin of inversions considering that breaks occur at either repetitive or non-homologous sequences. While inversions originating through the first mechanism might have a multiple origin, those originating through the latter mechanism would have a unique origin. Variation at regions flanking inversion breakpoints can be informative on the origin and history of inversions given the reduced recombination in heterokaryotypes. Here, we have analyzed nucleotide variation at a fragment flanking the most centromere-proximal shared breakpoint of several sequential overlapping inversions of the E chromosome of Drosophila subobscura —inversions E1, E2, E9 and E3. The molecular genealogy inferred from variation at this shared fragment does not exhi...

International Journal of Andrology, 2006

This paper reviews several studies that investigated the potential role of genetic factors in determining fertility outcomes. Our review demonstrates convincingly that fertility contains genetic variance; that is, differences between humans in their genetic make-up affects their fertility outcomes and fertilityrelated behaviours. This finding is robust using both heritabilities and coefficients of genetic variation, and using both direct measures of fertility outcomes and also fertility precursors like fecundity, marriage, fertility expectations and attempts to get pregnant (proception). Moreover, genetic variance can change over short periods of time or across educational levels, specifically for females, and the relevance of genetic variance seems to increase during times of increasing reproductive choice.

eLife, 2017

Chromosome inversions suppress genetic recombination and establish co-adapted gene complexes, or supergenes. The 2La inversion is a widespread polymorphism in the Anopheles gambiae species complex, the major African mosquito vectors of human malaria. Here we show that alleles of the 2La inversion are associated with natural malaria infection levels in wild-captured vectors from West and East Africa. Mosquitoes carrying the more-susceptible allele (2L+(a)) are also behaviorally less likely to be found inside houses. Vector control tools that target indoor-resting mosquitoes, such as bednets and insecticides, are currently the cornerstone of malaria control in Africa. Populations with high levels of the 2L+(a) allele may form reservoirs of persistent outdoor malaria transmission requiring novel measures for surveillance and control. The 2La inversion is a major and previously unappreciated component of the natural malaria transmission system in Africa, influencing both malaria suscept...

American journal of medical genetics. Part A, 2016

3q29 deletion syndrome is caused by a recurrent, typically de novo heterozygous 1.6 Mb deletion, but because incidence of the deletion is rare (1 in 30,000 births) the phenotype is not well described. To characterize the range of phenotypic manifestations associated with 3q29 deletion syndrome, we have developed an online registry (3q29deletion.org) for ascertainment of study subjects and phenotypic data collection via Internet-based survey instruments. We report here on data collected during the first 18 months of registry operation, from 44 patients. This is the largest cohort of 3q29 deletion carriers ever assembled and surveyed in a systematic way. Our data reveal that 28% of registry participants report neuropsychiatric phenotypes, including anxiety disorder, panic attacks, depression, bipolar disorder, and schizophrenia. Other novel findings include a high prevalence (64%) of feeding problems in infancy and reduced weight at birth for 3q29 deletion carriers (average reduction ...

Despite the interest in characterizing all genomic variation, the presence of large repeats at the breakpoints of many structural variants hinders their analysis. This is especially problematic in the case of inversions, since they are balanced changes without gain or loss of DNA. Here we tested novel linkage-based droplet digital PCR (ddPCR) assays on 20 inversions ranging from 3.1 to 742 kb and flanked by long inverted repeats (IRs) of up to 134 kb. Among these, we validated 13 inversions predicted by different genome-wide techniques. In addition, we have generated new experimental human population information across 95 African, European and East-Asian individuals for 16 of them, including four already known inversions for which there were no high-throughput methods to determine directly the orientation, like the well-characterized 17q21 inversion. Through comparison with previous data, independent replicates and both inversion breakpoints, we have demonstrated that the technique ...

Nature Communications

Inversions are one type of structural variants linked to phenotypic differences and adaptation in multiple organisms. However, there is still very little information about polymorphic inversions in the human genome due to the difficulty of their detection. Here, we develop a new high-throughput genotyping method based on probe hybridization and amplification, and we perform a complete study of 45 common human inversions of 0.1–415 kb. Most inversions promoted by homologous recombination occur recurrently in humans and great apes and they are not tagged by SNPs. Furthermore, there is an enrichment of inversions showing signatures of positive or balancing selection, diverse functional effects, such as gene disruption and gene-expression changes, or association with phenotypic traits. Therefore, our results indicate that the genome is more dynamic than previously thought and that human inversions have important functional and evolutionary consequences, making possible to determine for ...

2020

Background: Soybean oil is a complex mixture of five fatty acids (palmitic, stearic, oleic, linoleic, and linolenic). Soybean oil with a high oleic acid content is desirable because this monounsaturated fatty acid improves the oxidative stability of the oil. To investigate the genetic architecture of oleic acid in soybean seeds, 260 soybean germplasms from Northeast China were collected as natural populations. A genome-wide association study (GWAS) was conducted on a panel of 260 germplasm resources. Results: Phenotypic identification results showed that the oleic acid content varied from 8.2 to 35.0%. A total of 2, 311,337 single-nucleotide polymorphism (SNP) markers were obtained. GWAS analysis showed that there were many genes related to oleic acid content with a contribution rate of 7%. The candidate genes Glyma.11G229600.1 on chromosome 11 and Glyma.04G102900.1 on chromosome 4 were detected in a 2-year-long GWAS. The candidate gene Glyma.11G229600.1 showed a positive correlation with the oleic acid content, and the correlation coefficient was 0.980, while Glyma.04G102900.1 showed a negative correlation, with a coefficient of − 0.964. Conclusions: Glyma.04G102900.1 on chromosome 4 and Glyma.11G229600.1 on chromosome 11 were detected in both analyses (2018 and 2019). Glyma.04G102900.1 and Glyma.11G229600.1 are new key candidate genes related to oleic acid in soybean seeds. These results will be useful for high-oleic soybean breeding.

Interdisciplinary Sciences: Computational Life Sciences

Background Variations in the human genome have been studied extensively. However, little is known about the role of micro-inversions (MIs), generally defined as small (

BMC genomics, 2014

Turkey is a crossroads of major population movements throughout history and has been a hotspot of cultural interactions. Several studies have investigated the complex population history of Turkey through a limited set of genetic markers. However, to date, there have been no studies to assess the genetic variation at the whole genome level using whole genome sequencing. Here, we present whole genome sequences of 16 Turkish individuals resequenced at high coverage (32×-48×). We show that the genetic variation of the contemporary Turkish population clusters with South European populations, as expected, but also shows signatures of relatively recent contribution from ancestral East Asian populations. In addition, we document a significant enrichment of non-synonymous private alleles, consistent with recent observations in European populations. A number of variants associated with skin color and total cholesterol levels show frequency differentiation between the Turkish populations and E...

Population Genomics

The last decade has witnessed a myriad of advancements in the field of genomics, drastically changing our understanding of how genomes evolve; how genetic variation is maintained, gained, and lost; and how this variation affects gene function. In our opinion, the most relevant conceptual development has to be the renewed appreciation of the impact of genomic structural variation within species and across different species. In parallel, our newly gained ability to sequence the genomes collected from ancient populations has revolutionized how we conduct population and evolutionary genetics analyses. Combining these two exciting developments, we argue that studying the structural variation in ancient genomes will open new doors to previously unexplored areas of mammalian genome evolution. In this review, we summarize some of the recent developments in this field, most of which comes from studies in humans, and give an example where we determined the Neanderthal origins of a polymorphic gene deletion in humans combining information from modern and ancient genomes.

Genome biology, 2016

Inversion polymorphisms constitute an evolutionary puzzle: they should increase embryo mortality in heterokaryotypic individuals but still they are widespread in some taxa. Some insect species have evolved mechanisms to reduce the cost of embryo mortality but humans have not. In birds, a detailed analysis is missing although intraspecific inversion polymorphisms are regarded as common. In Australian zebra finches (Taeniopygia guttata), two polymorphic inversions are known cytogenetically and we set out to detect these two and potentially additional inversions using genomic tools and study their effects on embryo mortality and other fitness-related and morphological traits. Using whole-genome SNP data, we screened 948 wild zebra finches for polymorphic inversions and describe four large (12-63 Mb) intraspecific inversion polymorphisms with allele frequencies close to 50 %. Using additional data from 5229 birds and 9764 eggs from wild and three captive zebra finch populations, we show...

Proceedings of the National Academy of Sciences of the United States of America, 2017

Epidemiological and genetic association studies show that genetics play an important role in the attainment of education. Here, we investigate the effect of this genetic component on the reproductive history of 109,120 Icelanders and the consequent impact on the gene pool over time. We show that an educational attainment polygenic score, POLYEDU, constructed from results of a recent study is associated with delayed reproduction (P < 10(-100)) and fewer children overall. The effect is stronger for women and remains highly significant after adjusting for educational attainment. Based on 129,808 Icelanders born between 1910 and 1990, we find that the average POLYEDU has been declining at a rate of ∼0.010 standard units per decade, which is substantial on an evolutionary timescale. Most importantly, because POLYEDU only captures a fraction of the overall underlying genetic component the latter could be declining at a rate that is two to three times faster.

Journal of Human Genetics, 2013

a-synuclein (SNCA) is an established susceptibility gene for Parkinson's disease (PD), one of the most common human neurodegenerative disorders. Increased SNCA is considered to lead to PD and dementia with Lewy bodies. Four singlenucleotide polymorphisms (SNPs) in SNCA 3 0 region were prominently associated with PD among different ethnic groups. To examine how these SNPs influence disease susceptibility, we analyzed their potential effects on SNCA gene expression. We found that rs356219 showed allele-specific features. Gel shift assay using nuclear extracts from SH-SY5Y cells showed binding of one or more proteins to the protective allele, rs356219-A. We purified the rs356219-A-protein complex with DNA affinity beads and identified a bound protein using mass spectrometry. This protein, YY1 (Yin Yang 1), is an ubiquitous transcription factor with multiple functions. We next investigated SNCA expression change in SH-SY5Y cells by YY1 transfection. We also analyzed the expression of antisense noncoding RNA (ncRNA) RP11-115D19.1 in SNCA 3 0-flanking region, because rs356219 is located in intron of RP11-115D19.1. Little change was observed in SNCA expression levels; however, RP11-115D19.1 expression was prominently stimulated by YY1. In autopsied cortices, positive correlation was observed among RP11-115D19.1, SNCA and YY1 expression levels, suggesting their functional interactions in vivo. Knockdown of RP11-115D19.1 increased SNCA expression significantly in SH-SY5Y cells, suggesting its repressive effect on SNCA expression. Our findings of the protective allele-specific YY1 and antisense ncRNA raised a novel possible mechanism to regulate SNCA expression.

Expert Reviews in Molecular Medicine, 2009

Frontotemporal dementia (FTD) is a clinical syndrome with a heterogeneous molecular basis. Familial FTD has been linked to mutations in several genes, including those encoding the microtubule-associated protein tau (MAPT), progranulin (GRN), valosin-containing protein (VCP) and charged multivescicular body protein 2B (CHMP2B). The associated neuropathology is characterised by selective degeneration of the frontal and temporal lobes (frontotemporal lobar degeneration, FTLD), usually with the presence of abnormal intracellular protein accumulations. The current classification of FTLD neuropathology is based on the identity of the predominant protein abnormality, in the belief that this most closely reflects the underlying pathogenic process. Major subgroups include those characterised by the pathological tau, TDP-43, intermediate filaments and a group with cellular inclusions composed of an unidentified ubiquitinated protein. This review will focus on the current understanding of the molecular basis of each of the major FTLD subtypes. It is anticipated that this knowledge will provide the basis of future advances in the diagnosis and treatment of FTD.

BMC Genomics, 2015

Scientific Reports, 2016

Cocaine dependence is a complex psychiatric disorder involving both genetic and environmental factors. Several neurotransmitter systems mediate cocaine's effects, dependence and relapse, being the components of the neurotransmitter release machinery good candidates for the disorder. Previously, we identified a risk haplotype for cocaine dependence in the NSF gene, encoding the protein N-Ethylmaleimide-Sensitive Factor essential for synaptic vesicle turnover. Here we examined the possible contribution to cocaine dependence of a large copy number variant (CNV) that encompasses part of the NSF gene. We performed a case-control association study in a discovery sample (359 cases and 356 controls) and identified an association between cocaine dependence and the CNV (P = 0.013), that was confirmed in the replication sample (508 cases and 569 controls, P = 7.1e-03) and in a pooled analysis (P = 1.8e-04), with an over-representation of low number of copies in cases. Subsequently, we studied the functional impact of the CNV on gene expression and found that the levels of two NSF transcripts were significantly increased in peripheral blood mononuclear cells (PBMC) along with the number of copies of the CNV. These results, together with a previous study from our group, support the role of NSF in the susceptibility to cocaine dependence. Cocaine dependence is a complex psychiatric disorder that results from the interaction between genetic and environmental factors, with an estimated heritability of 65-79% 1-3. Cocaine inhibits dopamine, serotonin and norepinephrine reuptake by binding to their transporters (DAT1, SERT and NET, respectively), increasing their levels at the synaptic cleft 4,5. Also, other neurotransmitter pathways participate in cocaine dependence, withdrawal or relapse, including the glutamatergic, GABAergic and endocannabinoid systems 6-12. Their involvement in mediating cocaine effects and dependence makes the molecular machinery that controls neurotransmitter release to the synaptic cleft a strong candidate for participating in the development of cocaine dependence. As part of this complex process that involves many different proteins, the N-ethylmaleimide sensitive factor (NSF) plays an essential role in the synaptic vesicle turnover. NSF is responsible for the recycling of Soluble NSF Attachment

Science, 2007

The lack of association of the abnormal spindle-like microcephaly associated (ASPM) and Microcephalin (MCPH1) genes with brain size or intelligence described by Timpson et al. has been reported previously, including by our own group. Moreover, as in most studies of selection, our analyses were entirely independent of phenotypic association. We also respond to the previously published comment by Yu et al., which argued that ASPM has not undergone positive selection.

Genes

Chromosomal inversions are important drivers of genome evolution. The Eurasian malaria vector Anopheles messeae has five polymorphic inversions. A cryptic species, An. daciae, has been discriminated from An. messeae based on five fixed nucleotide substitutions in the internal transcribed spacer 2 (ITS2) of ribosomal DNA. However, the inversion polymorphism in An. daciae and the genome divergence between these species remain unexplored. In this study, we sequenced the ITS2 region and analyzed the inversion frequencies of 289 Anopheles larvae specimens collected from three locations in the Moscow region. Five individual genomes for each of the two species were sequenced. We determined that An. messeae and An. daciae differ from each other by the frequency of polymorphic inversions. Inversion X1 was fixed in An. messeae but polymorphic in An. daciae populations. The genome sequence comparison demonstrated genome-wide divergence between the species, especially pronounced on the inversio...

Nature reviews. Genetics, 2015

The discovery of genetic variation and the assembly of genome sequences are both inextricably linked to advances in DNA-sequencing technology. Short-read massively parallel sequencing has revolutionized our ability to discover genetic variation but is insufficient to generate high-quality genome assemblies or resolve most structural variation. Full resolution of variation is only guaranteed by complete de novo assembly of a genome. Here, we review approaches to genome assembly, the nature of gaps or missing sequences, and biases in the assembly process. We describe the challenges of generating a complete de novo genome assembly using current technologies and the impact that being able to perfectly sequence the genome would have on understanding human disease and evolution. Finally, we summarize recent technological advances that improve both contiguity and accuracy and emphasize the importance of complete de novo assembly as opposed to read mapping as the primary means to understand...

Genome research, 2018

For many years, inversions have been proposed to be a direct driving force in speciation since they suppress recombination when heterozygous. Inversions are the most common large-scale differences among humans and great apes. Nevertheless, they represent large events easily distinguishable by classical cytogenetics, whose resolution, however, is limited. Here, we performed a genome-wide comparison between human, great ape, and macaque genomes using the net alignments for the most recent releases of genome assemblies. We identified a total of 156 putative inversions, between 103 kb and 91 Mb, corresponding to 136 human loci. Combining literature, sequence, and experimental analyses, we analyzed 109 of these loci and found 67 regions inverted in one or multiple primates, including 28 newly identified inversions. These events overlap with 81 human genes at their breakpoints, and seven correspond to sites of recurrent rearrangements associated with human disease. This work doubles the n...

Human Mutation, 2013

Even with significant advances in technology, few studies of structural variation have yet resolved to the level of the precise nucleotide junction. We examined the sequence of 408,532 gains, 383,804 losses, and 166 inversions from the first sequenced personal genome, to quantify the relative proportion of mutational mechanisms. Among small variants (<1 kb), we observed that 72.6% of them were associated with nonhomologous processes and 24.9% with microsatellites events. Medium-size variants (<10 kb) were commonly related to minisatellites (25.8%) and retrotransposons (24%), whereas 46.2% of large variants (>10 kb) were associated with nonallelic homologous recombination. We genotyped eight new breakpoint-resolved inversions at (3q26.1, Xp11.22, 7q11.22, 16q23.1, 4q22.1, 1q31.3, 6q27, and 16q24.1) in human populations to elucidate the structure of these presumed benign variants. Three of these inversions (3q26.1, 7q11.22, and 16q23.1) were accompanied by unexpected complex rearrangements. In particular, the 16q23.1 inversion and an accompanying deletion would create conjoined chymotrypsinogen genes (CTRB1 and CTRB2), disrupt their gene structure, and exhibit differentiated allelic frequencies among populations. Also, two loci (Xp11.3 and 6q27) of potential reference assembly orientation errors were found. This study provides a thorough account of formation mechanisms for structural variants, and reveals a glimpse of the dynamic structure of inversions.

Evolution, 2017

Chromosome inversions have fascinated the scientific community, mainly because of their role in the rapid adaption of different taxa to changing environments. However, the ecological traits linked to chromosome inversions have been poorly studied. Here, we investigated the roles played by 23 chromosome inversions in the adaptation of the four major African malaria mosquitoes to local environments in Africa. We studied their distribution patterns by using spatially explicit modeling and characterized the ecogeographical determinants of each inversion range. We then performed hierarchical clustering and constrained ordination analyses to assess the spatial and ecological similarities among inversions. Our results show that most inversions are environmentally structured, suggesting that they are actively involved in processes of local adaptation. Some inversions exhibited similar geographical patterns and ecological requirements among the four mosquito species, providing evidence for parallel evolution. Conversely, common inversion polymorphisms between sibling species displayed divergent ecological patterns, suggesting that they might have a different adaptive role in each species. These results are in agreement with the finding that chromosomal inversions play a role in Anopheles ecotypic adaptation. This study establishes a strong ecological basis for future genome-based analyses to elucidate the genetic mechanisms of local adaptation in these four mosquitoes.

BMC Genomics, 2021

Background The Muscovy duck (Cairina moschata) is an economically important duck species, with favourable growth and carcass composition parameters in comparison to other ducks. However, limited genomic resources for Muscovy duck hinder our understanding of its evolution and genetic diversity. Results We combined linked-reads sequencing technology and reference-guided methods for de novo genome assembly. The final draft assembly was 1.12 Gbp with 29 autosomes, one sex chromosome and 4,583 unlocalized scaffolds with an N50 size of 77.35 Mb. Based on universal single-copy orthologues (BUSCO), the draft genome assembly completeness was estimated to be 93.30 %. Genome annotation identified 15,580 genes, with 15,537 (99.72 %) genes annotated in public databases. We conducted comparative genomic analyses and found that species-specific and rapidly expanding gene families (compared to other birds) in Muscovy duck are mainly involved in Calcium signaling, Adrenergic signaling in cardiomyocy...

Brazilian Journal of Biology, 2014

Kerodon acrobata is a caviidae rodent endemic from Brazilian Cerrado. It was described only in 1997 and the data about it is very scarce. The aim of this work was to characterize the karyotype of K. acrobata. Giemsa staining, nucleolar organizer region (NOR) banding, C-positive heterochromatin banding and DAPI fluorescence were used in N metaphases of a specimen collected in Asa Branca Farm, in Aurora do Tocantins municipality, Tocantins state, Brazil. K. acrobata showed the same diploid number, fundamental number and chromosome morphology as Kerodon rupestris. But its NOR location and heterochromatin distribution patterns indicated a unique cytogenetic profile when compared to its sister species, emphasizing the evolutionary uniqueness of this relatively new and unknown species. This record also extends the distribution of this species northward.

BMC Genomics, 2007

Background The zebrafish (Danio rerio) is an important vertebrate model organism system for biomedical research. The syntenic conservation between the zebrafish and human genome allows one to investigate the function of human genes using the zebrafish model. To facilitate analysis of the zebrafish genome, genetic maps have been constructed and sequence annotation of a reference zebrafish genome is ongoing. However, the duplicative nature of teleost genomes, including the zebrafish, complicates accurate assembly and annotation of a representative genome sequence. Cytogenetic approaches provide &quot;anchors&quot; that can be integrated with accumulating genomic data. Results Here, we cytogenetically define the zebrafish genome by first estimating the size of each linkage group (LG) chromosome using flow cytometry, followed by the cytogenetic mapping of 575 bacterial artificial chromosome (BAC) clones onto metaphase chromosomes. Of the 575 BAC clones, 544 clones localized to apparentl...

Journal of Human Genetics, 2012

Albright's hereditary osteodystrophy (AHO) is characterized by short stature, round face, calcifications, obesity, brachydactyly and intellectual disability. AHO without hormone resistance is called pseudopseudohypoparathyroidism (PPHP), a rare clinical condition difficult to diagnose with highly variable features. PPHP is caused by paternally inherited loss-of-function mutations in the GNAS. Patients with 2q37 microdeletions or HDAC4 mutations are also defined as having an AHO-like phenotype with normal stimulatory G (Gs) function. We have studied 256 patients with AHO features but no other diagnosis. Their platelet Gs activity was determined via the aggregation-inhibition test showing Gs hypo-or hyperfuncton in 24% and 15% of the patients, respectively. Before initiating with detailed (epi)genetic GNAS studies, we here wanted to excluded copy number variants (CNVs) in GNAS as cause of AHO with a novel large-scale screening technique. Multiplex amplicon quantification (MAQ) for CNVs screening was developed for the 20q13.3 region including GNAS and potential long-range imprinting control elements such as STX16. This is the first large-scale GNAS CNV study in patients with common AHO features but no CNVs were detected. In conclusion, CNVs in the GNAS region are not likely to cause an AHO-like phenotype with or without abnormal platelet Gs activity. Future studies will be undertaken to find out whether these AHO patients with abnormal Gs function are characterized by GNAS coding or methylation defects.

2021

ABSTRACTThe genetic makeup of an individual contributes to susceptibility and response to viral infection. While environmental, clinical and social factors play a role in exposure to SARS-CoV-2 and COVID-19 disease severity, host genetics may also be important. Identifying host-specific genetic factors indicate biological mechanisms of therapeutic relevance and clarify causal relationships of modifiable environmental risk factors for SARS-CoV-2 infection and outcomes. We formed a global network of researchers to investigate the role of human genetics in SARS-COV-2 infection and COVID-19 severity. We describe the results of three genome-wide association meta-analyses comprising up to 49,562 COVID-19 patients from 46 studies across 19 countries worldwide. We reported 13 genome-wide significant loci that are associated with SARS-CoV-2 infection or severe manifestations of COVID-19. Several of these loci correspond to previously documented associations to lung or autoimmune and inflamma...

Molecular Psychiatry, 2009

A concatenation of findings from preclinical and clinical studies support a preeminent function for the corticotropin-releasing factor (CRF) system in mediating the physiological response to external stressors and in the pathophysiology of anxiety and depression. Recently, human genetic studies have provided considerable support to several long-standing hypotheses of mood and anxiety disorders, including the CRF hypothesis. These data, reviewed in this report, are congruent with the hypothesis that this system is of paramount importance in mediating stress-related psychopathology. More specifically, variants in the gene encoding the CRF 1 receptor interact with adverse environmental factors to predict risk for stress-related psychiatric disorders. In-depth characterization of these variants will likely be important in furthering our understanding of the long-term consequences of adverse experience.

Science, 2019

Adaptive archaic hominin genes As they migrated out of Africa and into Europe and Asia, anatomically modern humans interbred with archaic hominins, such as Neanderthals and Denisovans. The result of this genetic introgression on the recipient populations has been of considerable interest, especially in cases of selection for specific archaic genetic variants. Hsieh et al. characterized adaptive structural variants and copy number variants that are likely targets of positive selection in Melanesians. Focusing on population-specific regions of the genome that carry duplicated genes and show an excess of amino acid replacements provides evidence for one of the mechanisms by which genetic novelty can arise and result in differentiation between human genomes. Science , this issue p. eaax2083

BMC Bioinformatics, 2018

Background: The advent of next-generation sequencing (NGS) has made whole-genome sequencing of cohorts of individuals a reality. Primary datasets of raw or aligned reads of this sort can get very large. For scientific questions where curated called variants are not sufficient, the sheer size of the datasets makes analysis prohibitively expensive. In order to make re-analysis of such data feasible without the need to have access to a large-scale computing facility, we have developed a highly scalable, storage-agnostic framework, an associated API and an easy-to-use web user interface to execute custom filters on large genomic datasets. Results: We present BAMSI, a Software as-a Service (SaaS) solution for filtering of the 1000 Genomes phase 3 set of aligned reads, with the possibility of extension and customization to other sets of files. Unique to our solution is the capability of simultaneously utilizing many different mirrors of the data to increase the speed of the analysis. In particular, if the data is available in private or public clouds-an increasingly common scenario for both academic and commercial cloud providers-our framework allows for seamless deployment of filtering workers close to data. We show results indicating that such a setup improves the horizontal scalability of the system, and present a possible use case of the framework by performing an analysis of structural variation in the 1000 Genomes data set. Conclusions: BAMSI constitutes a framework for efficient filtering of large genomic data sets that is flexible in the use of compute as well as storage resources. The data resulting from the filter is assumed to be greatly reduced in size, and can easily be downloaded or routed into e.g. a Hadoop cluster for subsequent interactive analysis using Hive, Spark or similar tools. In this respect, our framework also suggests a general model for making very large datasets of high scientific value more accessible by offering the possibility for organizations to share the cost of hosting data on hot storage, without compromising the scalability of downstream analysis.

PLoS ONE, 2014

Long non-coding RNAs are a new class of non-coding RNAs that are at the crosshairs in many human diseases such as cancers, cardiovascular disorders, inflammatory and autoimmune disease like Inflammatory Bowel Disease (IBD) and Type 1 Diabetes (T1D). Nearly 90% of the phenotype-associated single-nucleotide polymorphisms (SNPs) identified by genomewide association studies (GWAS) lie outside of the protein coding regions, and map to the non-coding intervals. However, the relationship between phenotype-associated loci and the non-coding regions including the long non-coding RNAs (lncRNAs) is poorly understood. Here, we systemically identified all annotated IBD and T1D loci-associated lncRNAs, and mapped nominally significant GWAS/ImmunoChip SNPs for IBD and T1D within these lncRNAs. Additionally, we identified tissue-specific cis-eQTLs, and strong linkage disequilibrium (LD) signals associated with these SNPs. We explored sequence and structure based attributes of these lncRNAs, and also predicted the structural effects of mapped SNPs within them. We also identified lncRNAs in IBD and T1D that are under recent positive selection. Our analysis identified putative lncRNA secondary structure-disruptive SNPs within and in close proximity (+/25 kb flanking regions) of IBD and T1D loci-associated candidate genes, suggesting that these RNA conformation-altering polymorphisms might be associated with diseasedphenotype. Disruption of lncRNA secondary structure due to presence of GWAS SNPs provides valuable information that could be potentially useful for future structure-function studies on lncRNAs.

Proceedings of the National Academy of Sciences, 2006

Copy number variation is surprisingly common among humans and can be involved in phenotypic diversity and variable susceptibility to complex diseases, but little is known of the extent of copy number variation in nonhuman primates. We have used two array-based comparative genomic hybridization platforms to identify a total of 355 copy number variants (CNVs) in the genomes of 20 wild-born chimpanzees ( Pan troglodytes ) and have compared the identified chimpanzee CNVs to known human CNVs from previous studies. Many CNVs were observed in the corresponding regions in both chimpanzees and humans; especially those CNVs of higher frequency. Strikingly, these loci are enriched 20-fold for ancestral segmental duplications, which may facilitate CNV formation through nonallelic homologous recombination mechanisms. Therefore, some of these regions may be unstable “hotspots” for the genesis of copy number variation, with recurrent duplications and deletions occurring across and within species.

An important step towards the development of treatments for cognitive impairment in ageing and neurodegenerative diseases is to identify genetic and environmental modifiers of cognitive function and understand the mechanism by which they exert an effect. In Huntington’s disease, the most common autosomal dominant dementia, a small number of studies have identified intellectual enrichment, i.e. a cognitively stimulating lifestyle, and genetic polymorphisms as potential modifiers of cognitive function. The aim of our study was to further investigate the relationship and interaction between genetic factors and intellectual enrichment on cognitive function and brain atrophy in Huntington’s disease. For this purpose, we analysed data from Track- HD, a multi-centre longitudinal study in Huntington’s disease gene-carriers, and focused on the role of intellectual enrichment (estimated at baseline) and the genes FAN1, MSH3, BDNF, COMT and MAPT in predicting cognitive decline and brain atroph...

2020

ABSTRACTGenome-wide association studies (GWAS) have identified thousands of variants associated with disease phenotypes. However, the majority of these variants do not alter coding sequences, making it difficult to assign their function. To this end, we present a multi-omic epigenetic atlas of the adult human brain through profiling of the chromatin accessibility landscapes and three-dimensional chromatin interactions of seven brain regions across a cohort of 39 cognitively healthy individuals. Single-cell chromatin accessibility profiling of 70,631 cells from six of these brain regions identifies 24 distinct cell clusters and 359,022 cell type-specific regulatory elements, capturing the regulatory diversity of the adult brain. We develop a machine learning classifier to integrate this multi-omic framework and predict dozens of functional single nucleotide polymorphisms (SNPs), nominating gene and cellular targets for previously orphaned GWAS loci. These predictions both inform well...

Nature Genetics, 2020

curated the frozen tissue specimens used in this work. COMPETING INTERESTS STATEMENT H.Y.C. is a co-founder of Accent Therapeutics, Boundless Bio, and an advisor to 10x Genomics, Arsenal Biosciences, Spring Discovery. S.B.M. is on the scientific advisory board of MyOme. A.K. is a consultant for Biogen Inc. A.S. is a consultant for MyoKardia. W.J.G. is a consultant for Guardant Health, 10x Genomics, and Protillion Biosciences. DATA AVAILABILITY All data generated in this work are available through GEO accession GSE147672. https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi? acc=GSE147672 To facilitate broad access to our data, we have created a WashU Epigenome browser session (Session ID: drS3o1n4kJ) for our scATAC-seq data in the following track formats: (i) broad cell types ("Corces_scATAC_BroadCellTypes"), (ii) broad clusters ("Corces_scATAC_BroadClusters"), (iii) neuron subclusters ("Corces_scATAC_NeuronSubClusters"), and (iv) neuron subclustered cell types / LDSC groups ("Corces_scATAC_NeuronSubCellTypes"). These tracks are accessible via the following link-http:// epigenomegateway.wustl.edu/legacy/?genome=hg38&session=drS3o1n4kJ.

PLoS ONE, 2013

Meiotic recombination is sexually dimorphic in most mammalian species, including humans, but the basis for the male:female differences remains unclear. In the present study, we used cytological methodology to directly compare recombination levels between human males and females, and to examine possible sex-specific differences in upstream events of double-strand break (DSB) formation and synaptic initiation. Specifically, we utilized the DNA mismatch repair protein MLH1 as a marker of recombination events, the RecA homologue RAD51 as a surrogate for DSBs, and the synaptonemal complex proteins SYCP3 and/or SYCP1 to examine synapsis between homologs. Consistent with linkage studies, genome-wide recombination levels were higher in females than in males, and the placement of exchanges varied between the sexes. Subsequent analyses of DSBs and synaptic initiation sites indicated similar male:female differences, providing strong evidence that sex-specific differences in recombination rates are established at or before the formation of meiotic DSBs. We then asked whether these differences might be linked to variation in the organization of the meiotic axis and/or axis-associated DNA and, indeed, we observed striking male:female differences in synaptonemal complex (SC) length and DNA loop size. Taken together, our observations suggest that sex specific differences in recombination in humans may derive from chromatin differences established prior to the onset of the recombination pathway.

Frontiers in Genetics

Behçet disease (BD) is a polygenic, multifactorial, multisystem inflammatory condition with unknown etiology. Global distribution of BD is geographically structured, highest prevalence observed among East Asian, Middle Eastern, and Mediterranean populations. Although adaptive selection on a few BD susceptibility loci is speculated, a thorough evolutionary analysis on the genetic architecture of BD is lacking. We aimed to understand whether increased BD risk in the human populations with high prevalence is due to past selection on BD associated genes. We performed population genetics analyses with East Asian (high BD prevalence), European (low/very low BD prevalence), and African (very low/no BD prevalence) populations. Comparison of ancestral and derived alleles’ frequencies versus their reported susceptible or protective effect on BD showed both derived and ancestral alleles are associated with increased BD risk. Variants showing higher risk to and more significant association with...

Heredity, 2010

Chromosomal inversions have been of long-standing interest to geneticists because they are capable of suppressing recombination and facilitating the formation of adaptive gene complexes. An exceptional inversion polymorphism (ZAL2 m) in the white-throated sparrow (Zonotrichia albicollis) is linked to variation in plumage, social behavior and mate choice, and is maintained in the population by negative assortative mating. The ZAL2 m polymorphism is a complex inversion spanning 4100 Mb and has been proposed to be a strong suppressor of recombination, as well as a potential model for studying neo-sex chromosome evolution. To quantify and evaluate these features of the ZAL2 m polymorphism, we generated sequence from 8 ZAL2 m and 16 ZAL2 chromosomes at 58 loci inside and 4 loci outside the inversion. Inside the inversion we found that recombination was completely suppressed between ZAL2 and ZAL2 m , resulting in uniformly high levels of genetic differentiation (F ST ¼ 0.94), the formation of two distinct haplotype groups representing the alternate chromosome arrangements and extensive linkage disequilibrium spanning B104 Mb within the inversion, whereas gene flow was not suppressed outside the inversion. Finally, although ZAL2 m homozygotes are exceedingly rare in the population, occurring at a frequency of o1%, we detected evidence of historical recombination between ZAL2 m chromosomes inside the inversion, refuting its potential status as a non-recombining autosome.

PLOS Genetics, 2019

Polymorphic inversions contribute to adaptation and phenotypic variation. However, large multi-centric association studies of inversions remain challenging. We present scoreInvHap, a method to genotype inversions from SNP data for genome-wide association studies (GWASs), overcoming important limitations of current methods and outperforming them in accuracy and applicability. scoreInvHap calls individual inversion-genotypes from a similarity score to the SNPs of experimentally validated references. It can be used on different sources of SNP data, including those with low SNP coverage such as exome sequencing, and is easily adaptable to genotype new inversions, either in humans or in other species. We present 20 human inversions that can be reliably and easily genotyped with scoreInv-Hap to discover their role in complex human traits, and illustrate a first genome-wide association study of experimentally-validated human inversions. scoreInvHap is implemented in R and it is freely available from Bioconductor.

Summary The Eurasian Holocene (beginning c. 12 thousand years ago) encompassed some of the most significant changes in human evolution, with far-reaching consequences for the dietary, physical and mental health of present-day populations. Using an imputed dataset of &gt;1600 complete ancient genome sequences, and new computational methods for locating selection in time and space, we reconstructed the selection landscape of the transition from hunting and gathering, to farming and pastoralism across West Eurasia. We identify major selection signals related to metabolism, possibly associated with the dietary shift occurring in this period. We show that the selection on loci such as the FADS cluster, associated with fatty acid metabolism, and the lactase persistence locus, began earlier than previously thought. A substantial amount of selection is also found in the HLA region and other loci associated with immunity, possibly due to the increased exposure to pathogens during the Neolith...

Movement Disorders, 2019

Background: Genetic variation at the microtubule-associated protein tau locus is associated with clinical parkinsonism. However, it is unclear as to whether microtubule-associated protein tau H1 subhaplotypes are associated with the burden of neuropathological features of Lewy body disease. Objectives: To evaluate associations of microtubule-associated protein tau haplotypes with severity of Lewy body pathology and markers of SN neuronal loss in Lewy body disease cases. Methods: Five hundred eighty-five autopsy-confirmed Lewy body disease cases were included. Six microtubule-associated protein tau variants (rs1467967, rs242557, rs3785883, rs2471738, rs8070723, and rs7521) were genotyped to define common microtubule-associated protein tau haplotypes. Lewy body counts were measured in five cortical regions. Ventrolateral and medial SN neuronal loss were assessed semiquantitatively. Nigrostriatal dopaminergic degeneration was quantified by image analysis of tyrosine hydroxylase immunoreactivity in the dorsolateral and ventromedial putamen.

Twin Research and Human Genetics, 2014

Chromosome 17q21.31 microdeletion syndrome is a genomic disorder caused by a recurrent 600 kb long deletion. The deletion affects the region of a common inversion present in about 20% of Europeans. The inversion is associated with the H2 haplotype carrying additional low-copy repeats susceptible to non-allelic homologous recombination, and this haplotype is prone to deletion. No instances of 17q21.31 deletions inherited from an affected parent have been reported, and the deletions always affected a parental chromosome with the H2 haplotype. The syndrome is characterized clinically by intellectual disability, hypotonia, friendly behavior and specific facial dysmorphism with long face, large tubular or pear-shaped nose and bulbous nasal tip. We present monozygotic twin sisters showing the typical clinical picture of the syndrome. The phenotype of the sisters was very similar, with a slightly more severe presentation in Twin B. The 17q21.31 microdeletion was confirmed in both patients ...

Nature, 2005

Gene and duplication structure analysis Although most (66%) of the autosomal base pairs (bp) duplicated in humans are shared between human and chimpanzee (Table 1), a

Genome Biology, 2016

Aside from inheriting half of the genome of each of our parents, we are born with a small number of novel mutations that occurred during gametogenesis and postzygotically. Recent genome and exome sequencing studies of parent-offspring trios have provided the first insights into the number and distribution of these de novo mutations in health and disease, pointing to risk factors that increase their number in the offspring. De novo mutations have been shown to be a major cause of severe early-onset genetic disorders such as intellectual disability, autism spectrum disorder, and other developmental diseases. In fact, the occurrence of novel mutations in each generation explains why these reproductively lethal disorders continue to occur in our population. Recent studies have also shown that de novo mutations are predominantly of paternal origin and that their number increases with advanced paternal age. Here, we review the recent literature on de novo mutations, covering their detection, biological characterization, and medical impact.

2018

BackgroundThe skew in distribution of handedness is a uniquely human trait, and has fascinated researchers for centuries. The heritability of handedness is estimated at 25%, but defining genetic variants contributing to this trait has so far proved elusive.MethodsWe performed GWAS of self-reported handedness in UK Biobank, a prospective cohort study of ∼500,000 individuals. Furthermore, we investigated correlations between our associated SNPs and brain imaging-derived phenotypes (IDPs) from &gt;9,000 individuals in UK Biobank, as well as between self-reported handedness and IDPs.ResultsOur association study of 38,322 left-handers vs 356,567 right-handers (excluding ambidextrous participants) revealed three genome-wide significant loci (rs199512, 17q21.31, p=4.1x10−9; rs45608532, 22q11.22, p=1.4x10−8; rs13017199, 2q34, p=3.3x10−8). In the imaging study, we found strong associations between rs199512 and diffusion MRI measures mainly in white matter tracts connecting language-related b...

Frontiers in Cellular Neuroscience, 2020

DNA rearrangements are important in various contexts, such as in vertebrate immunity, and cancer genome instability. The single-celled eukaryoteOxytricha trifallaxundergoes massive and reproducible genome rearrangement during post-zygotic development, making it a compelling model organism to study DNA rearrangements. To date, computational tools for the extraction and analysis of rearrangement annotations lack transparency and rely on assumptions that may not hold for all analyzed data, leading to irreproducibility of results and loss of information through data filtering or misrepresentation.An implementation of a procedure for the annotation and analysis of DNA rearrangement as a web application is discussed and tested. The resulting annotations provide an improvement over previous annotations in the following manner. (a) SDRAP achieves more complete precursor-product mappings than previous software (b) the software allows for full transparency of all parameters used during the an...

Genome Medicine

Background High sequence identity between segmental duplications (SDs) can facilitate copy number variants (CNVs) via non-allelic homologous recombination (NAHR). These CNVs are one of the fundamental causes of genomic disorders such as the 3q29 deletion syndrome (del3q29S). There are 21 protein-coding genes lost or gained as a result of such recurrent 1.6-Mbp deletions or duplications, respectively, in the 3q29 locus. While NAHR plays a role in CNV occurrence, the factors that increase the risk of NAHR at this particular locus are not well understood. Methods We employed an optical genome mapping technique to characterize the 3q29 locus in 161 unaffected individuals, 16 probands with del3q29S and their parents, and 2 probands with the 3q29 duplication syndrome (dup3q29S). Long-read sequencing-based haplotype resolved de novo assemblies from 44 unaffected individuals, and 1 trio was used for orthogonal validation of haplotypes and deletion breakpoints. Results In total, we discovere...

Genes

Background: Intraocular pressure (IOP) is a major modifiable risk factor for glaucoma. However, the mechanisms underlying the controlling of IOP remain to be elucidated. Objective: To prioritize genes that are pleiotropically associated with IOP. Methods: We adopted a two-sample Mendelian randomization method, named summary-based Mendelian randomization (SMR), to examine the pleiotropic effect of gene expression on IOP. The SMR analyses were based on summarized data from a genome-wide association study (GWAS) on IOP. We conducted separate SMR analyses using Genotype-Tissue Expression (GTEx) and Consortium for the Architecture of Gene Expression (CAGE) expression quantitative trait loci (eQTL) data. Additionally, we performed a transcriptome-wide association study (TWAS) to identify genes whose cis-regulated expression levels were associated with IOP. Results: We identified 19 and 25 genes showing pleiotropic association with IOP using the GTEx and CAGE eQTL data, respectively. RP11-...

Nature Communications, 2019

Machine learning algorithms can be trained to estimate age from brain structural MRI. The difference between an individual’s predicted and chronological age, predicted age difference (PAD), is a phenotype of relevance to aging and brain disease. Here, we present a new deep learning approach to predict brain age from a T1-weighted MRI. The method was trained on a dataset of healthy Icelanders and tested on two datasets, IXI and UK Biobank, utilizing transfer learning to improve accuracy on new sites. A genome-wide association study (GWAS) of PAD in the UK Biobank data (discovery set: $$N=12378$$ N = 12378 , replication set: $$N=4456$$ N = 4456 ) yielded two sequence variants, rs1452628-T ($$\beta =-0.08$$ β = − 0.08 , $$P=1.15\times{10}^{-9}$$ P = 1.15 × 10 − 9 ) and rs2435204-G ($$\beta =0.102$$ β = 0.102 , $$P=9.73\times 1{0}^{-12}$$ P = 9.73 × 1 0 − 12 ). The former is near KCNK2 and correlates with reduced sulcal width, whereas the latter correlates with reduced white matter surf...

Nature Genetics, 2012

are employees at deCODE genetics, a biotechnology company that provides genetic testing services, and own stock/stock options in the company. Jose Florez received consulting honoraria from Novartis, Lilly and Pfizer. Inês Barroso and spouse own stock in Glaxosmithkline and Incyte Ltd.

JAMA Psychiatry

IMPORTANCE Past studies have identified associations between brain macrostructure and alcohol use behaviors. However, identifying directional associations between these phenotypes is difficult due to the limitations of observational studies. OBJECTIVE To use mendelian randomization (MR) to identify directional associations between brain structure and alcohol use and elucidate the transcriptomic and cellular underpinnings of identified associations. DESIGN, SETTING, AND PARTICIPANTS The main source data comprised summary statistics from population-based and case-control genome-wide association studies (GWAS) of neuroimaging, behavioral, and clinical phenotypes (N = 763 874). Using these data, bidirectional and multivariable MR was performed analyzing associations between brain macrostructure and alcohol use. Downstream transcriptome-wide association studies (TWAS) and cell-type enrichment analyses investigated the biology underlying identified associations. The study approach was data driven and did not test any a priori hypotheses. Data were analyzed August 2021 to May 2022. MAIN OUTCOMES AND MEASURES Brain structure phenotypes (global cortical thickness [GCT] and global cortical surface area [GCSA] in 33 709 individuals and left-right subcortical volumes in 19 629 individuals) and alcohol use behaviors (alcoholic drinks per week [DPW] in 537 349 individuals, binge drinking frequency in 143 685 individuals, and alcohol use disorder in 8845 individuals vs 20 657 control individuals [total of 29 502]). RESULTS The main bidirectional MR analyses were performed in samples totaling 763 874 individuals, among whom more than 94% were of European ancestry, 52% to 54% were female, and the mean cohort ages were 40 to 63 years. Negative associations were identified between genetically predicted GCT and binge drinking (β, −2.52; 95% CI, −4.13 to −0.91) and DPW (β, −0.88; 95% CI, −1.37 to −0.40) at a false discovery rate (FDR) of 0.05. These associations remained significant in multivariable MR models that accounted for neuropsychiatric phenotypes, substance use, trauma, and neurodegeneration. TWAS of GCT and alcohol use behaviors identified 5 genes at the 17q21.31 locus oppositely associated with GCT and binge drinking or DPW (FDR = 0.05). Cell-type enrichment analyses implicated glutamatergic cortical neurons in alcohol use behaviors. CONCLUSIONS AND RELEVANCE The findings in this study show that the associations between GCT and alcohol use may reflect a predispositional influence of GCT and that 17q21.31 genes and glutamatergic cortical neurons may play a role in this association. While replication studies are needed, these findings should enhance the understanding of associations between brain structure and alcohol use.

Nature Genetics, 2012

During aging, intracranial volume remains unchanged and represents maximally attained brain size, while various interacting biological phenomena lead to brain volume loss. Consequently, intracranial volume and brain volume in late life reflect different genetic influences. Our genomewide association study in 8,175 community-dwelling elderly did not reveal any genome-wide significant associations (p<5*10 −8) for brain volume. In contrast, intracranial volume was significantly associated with two loci: rs4273712 (p=3.4*10 −11), a known height locus on chromosome 6q22, and rs9915547, tagging the inversion on chromosome 17q21 (p=1.5*10 −12). We replicated the associations of these loci with intracranial volume in a separate sample of 1,752 older persons (p=1.1*10 −3 for 6q22 and p=1.2*10 −3 for 17q21). Furthermore, we also found suggestive associations of the 17q21 locus with head circumference in 10,768 children (mean age 14.5 months). Our data identify two loci associated with head size, with the inversion on 17q21 also likely involved in attaining maximal brain size.

Molecular Ecology, 2017

The evolution of complex traits in heterogeneous environments may shape the order of genes within chromosomes. Drosophila pseudoobscura has a rich gene arrangement polymorphism that allows one to test evolutionary genetic hypotheses about how chromosomal inversions are established in populations. D. pseudoobscura has >30 gene arrangements on a single chromosome that were generated through a series of overlapping inversion mutations with > 10 inversions with appreciable frequencies and wide geographic distributions. This study analyzes the genomic sequences of 54 strains of Drosophila pseudoobscura that carry one of six different chromosomal arrangements to test whether (1) genetic drift, (2) hitchhiking with an adaptive allele, (3) direct effects of inversions to create gene disruptions caused by breakpoints, or (4) indirect effects of inversions in limiting the formation of recombinant gametes are responsible for the establishment of new gene arrangements. We found that the inversion events do not disrupt the structure of protein coding genes at the breakpoints. Population genetic analyses of 2,669 protein coding genes identified 277 outlier loci harboring elevated frequencies of arrangement-specific derived alleles. Significant linkage disequilibrium occurs among distant loci interspersed between regions with low levels of association indicating that distant allelic combinations are held together despite shared polymorphism among arrangements. Outlier genes showing evidence of genetic differentiation between arrangements are enriched for sensory perception and detoxification genes. The data presented here support the indirect effect of inversion hypothesis where chromosomal inversions are favored because they maintain linked associations among multi-locus allelic combinations among different arrangements.

2017

SummaryThe genetic basis of brain structure and function is largely unknown. We carried out genome-wide association studies of 3,144 distinct functional and structural brain imaging derived phenotypes in UK Biobank (discovery dataset 8,428 subjects). We show that many of these phenotypes are heritable. We identify 148 clusters of SNP-imaging associations with lead SNPs that replicate at p&lt;0.05, when we would expect 21 to replicate by chance. Notable significant and interpretable associations include: iron transport and storage genes, related to changes in T2* in subcortical regions; extracellular matrix and the epidermal growth factor genes, associated with white matter micro-structure and lesion volume; genes regulating mid-line axon guidance development associated with pontine crossing tract organisation; and overall 17 genes involved in development, pathway signalling and plasticity. Our results provide new insight into the genetic architecture of the brain with relevance to c...