The landscape of human STR variation

Short tandem repeats are among the most polymorphic loci in the human genome. These loci play a role in the etiology of a range of genetic diseases and have been frequently utilized in forensics, population genetics, and genetic genealogy. Despite this plethora of applications, little is known about the variation of most STRs in the human population. Here, we report the largest-scale analysis of human STR variation to date. We collected information for nearly 700,000 STR loci across more than 1000 individuals in Phase 1 of the 1000 Genomes Project. Extensive quality controls show that reliable allelic spectra can be obtained for close to 90% of the STR loci in the genome. We utilize this call set to analyze determinants of STR variation, assess the human reference genome’s representation of STR alleles, find STR loci with common loss-of-function alleles, and obtain initial estimates of the linkage disequilibrium between STRs and common SNPs. Overall, these analyses further elucidate the scale of genetic variation beyond classical point mutations.American Society for Engineering Education. National Defense Science and Engineering Graduate Fellowshi

Polymorphic tandem repeats within gene promoters act as modifiers of gene expression and DNA methylation in humans

Despite representing an important source of genetic variation, tandem repeats (TRs) remain poorly studied due to technical difficulties. We hypothesized that TRs can operate as expression (eQTLs) and methylation (mQTLs) quantitative trait loci. To test this we analyzed the effect of variation at 4849 promoter-associated TRs, genotyped in 120 individuals, on neighboring gene expression and DNA methylation. Polymorphic promoter TRs were associated with increased variance in local gene expression and DNA methylation, suggesting functional consequences related to TR variation. We identified >100 TRs associated with expression/methylation levels of adjacent genes. These potential eQTL/mQTL TRs were enriched for overlaps with transcription factor binding and DNaseI hypersensitivity sites, providing a rationale for their effects. Moreover, we showed that most TR variants are poorly tagged by nearby single nucleotide polymorphisms (SNPs) markers, indicating that many functional TR variants are not effectively assayed by SNP-based approaches. Our study assigns biological significance to TR variations in the human genome, and suggests that a significant fraction of TR variations exert functional effects via alterations of local gene expression or epigenetics. We conclude that targeted studies that focus on genotyping TR variants are required to fully ascertain functional variation in the genome

Tandem repeat variation in human and great ape populations and its impact on gene expression divergence

Póster presentado en la Annual Meeting of the Society for Molecular Biology and Evolution (SMBE), celebrada en Viena del 12 al 16 de julio de 2015.Tandem repeats (TR) are stretches of DNA that are highly variable in length and mutate rapidly, and thus an important source of genetic variation. This variation is highly informative for population and conservation genetics, and has also been associated with several pathological conditions and with gene expression regulation. However, genome-wide surveys of TR variation in humans and close species have been scarce due to the technical difficulties derived from short-read technology.Peer Reviewe

A variant in TAF1 is associated with a new syndrome with severe intellectual disability and characteristic dysmorphic features

We describe the discovery of a new genetic syndrome, RykDax syndrome, driven by a whole genome sequencing (WGS) study of one family from Utah with two affected male brothers, presenting with severe intellectual disability (ID), a characteristic intergluteal crease, and very distinctive facial features including a broad, upturned nose, sagging cheeks, downward sloping palpebral fissures, prominent periorbital ridges, deep-set eyes, relative hypertelorism, thin upper lip, a high-arched palate, prominent ears with thickened helices, and a pointed chin. This Caucasian family was recruited from Utah, USA. Illumina-based WGS was performed on 10 members of this family, with additional Complete Genomics-based WGS performed on the nuclear portion of the family (mother, father and the two affected males). Using WGS datasets from 10 members of this family, we can increase the reliability of the biological inferences with an integrative bioinformatic pipeline. In combination with insights from clinical evaluations and medical diagnostic analyses, these DNA sequencing data were used in the study of three plausible genetic disease models that might uncover genetic contribution to the syndrome. We found a 2 to 5-fold difference in the number of variants detected as being relevant for various disease models when using different sets of sequencing data and analysis pipelines. We derived greater accuracy when more pipelines were used in conjunction with data encompassing a larger portion of the family, with the number of putative de-novo mutations being reduced by 80%, due to false negative calls in the parents. The boys carry a maternally inherited missense variant in a X-chromosomal gene TAF1, which we consider as disease relevant. TAF1 is the largest subunit of the general transcription factor IID (TFIID) multi-protein complex, and our results implicate mutations in TAF1 as playing a critical role in the development of this new intellectual disability syndrome

Tandem repeat variation in human and great ape populations and its impact on gene expression divergence

Tandem repeats (TRs) are stretches of DNA that are highly variable in length and mutate rapidly. They are thus an important source of genetic variation. This variation is highly informative for population and conservation genetics. It has also been associated with several pathological conditions and with gene expression regulation. However, genome-wide surveys of TR variation in humans and closely related species have been scarce due to technical difficulties derived from short-read technology. Here we explored the genome-wide diversity of TRs in a panel of 83 human and nonhuman great ape genomes, in a total of six different species, and studied their impact on gene expression evolution. We found that population diversity patterns can be efficiently captured with short TRs (repeat unit length, 1-5 bp). We examined the potential evolutionary role of TRs in gene expression differences between humans and primates by using 30,275 larger TRs (repeat unit length, 2-50 bp). Genes that contained TRs in the promoters, in their 3' untranslated region, in introns, and in exons had higher expression divergence than genes without repeats in the regions. Polymorphic small repeats (1-5 bp) had also higher expression divergence compared with genes with fixed or no TRs in the gene promoters. Our findings highlight the potential contribution of TRs to human evolution through gene regulation.A.W. and T.B.S. acknowledge support through Swiss National Science Foundation grant 31003A_146137, as well as through the University Priority/nResearch Program in Evolutionary Biology at the University of Zurich. T.M.B. was supported by a European Research Council (ERC) starting grant (260372), ICREA, EMBO Young Investigator Award, and the Ministerio de Ciencia e Innovación (MICINN) (BFU2014-55090-P, Spain). This work was also supported by the National Institutes of Health (NIH) grants HG006696, MH097018, and DA033660, and by the March of Dimes Foundation grant 6-FY13-92

Tandem repeat variation in human and great ape populations and its impact on gene expression divergence

Tandem repeats (TRs) are stretches of DNA that are highly variable in length and mutate rapidly. They are thus an important source of genetic variation. This variation is highly informative for population and conservation genetics. It has also been associated with several pathological conditions and with gene expression regulation. However, genome-wide surveys of TR variation in humans and closely related species have been scarce due to technical difficulties derived from short-read technology. Here we explored the genome-wide diversity of TRs in a panel of 83 human and nonhuman great ape genomes, in a total of six different species, and studied their impact on gene expression evolution. We found that population diversity patterns can be efficiently captured with short TRs (repeat unit length, 1-5 bp). We examined the potential evolutionary role of TRs in gene expression differences between humans and primates by using 30,275 larger TRs (repeat unit length, 2-50 bp). Genes that contained TRs in the promoters, in their 3' untranslated region, in introns, and in exons had higher expression divergence than genes without repeats in the regions. Polymorphic small repeats (1-5 bp) had also higher expression divergence compared with genes with fixed or no TRs in the gene promoters. Our findings highlight the potential contribution of TRs to human evolution through gene regulation.A.W. and T.B.S. acknowledge support through Swiss National Science Foundation grant 31003A_146137, as well as through the University Priority/nResearch Program in Evolutionary Biology at the University of Zurich. T.M.B. was supported by a European Research Council (ERC) starting grant (260372), ICREA, EMBO Young Investigator Award, and the Ministerio de Ciencia e Innovación (MICINN) (BFU2014-55090-P, Spain). This work was also supported by the National Institutes of Health (NIH) grants HG006696, MH097018, and DA033660, and by the March of Dimes Foundation grant 6-FY13-92

Deep Phylogenetic Analysis of Haplogroup G1 Provides Estimates of SNP and STR Mutation Rates on the Human Y-Chromosome and Reveals Migrations of Iranic Speakers

<div><p>Y-chromosomal haplogroup G1 is a minor component of the overall gene pool of South-West and Central Asia but reaches up to 80% frequency in some populations scattered within this area. We have genotyped the G1-defining marker M285 in 27 Eurasian populations (n= 5,346), analyzed 367 M285-positive samples using 17 Y-STRs, and sequenced ~11 Mb of the Y-chromosome in 20 of these samples to an average coverage of 67X. This allowed detailed phylogenetic reconstruction. We identified five branches, all with high geographical specificity: G1-L1323 in Kazakhs, the closely related G1-GG1 in Mongols, G1-GG265 in Armenians and its distant brother clade G1-GG162 in Bashkirs, and G1-GG362 in West Indians. The haplotype diversity, which decreased from West Iran to Central Asia, allows us to hypothesize that this rare haplogroup could have been carried by the expansion of Iranic speakers northwards to the Eurasian steppe and via founder effects became a predominant genetic component of some populations, including the Argyn tribe of the Kazakhs. The remarkable agreement between genetic and genealogical trees of Argyns allowed us to calibrate the molecular clock using a historical date (1405 AD) of the most recent common genealogical ancestor. The mutation rate for Y-chromosomal sequence data obtained was 0.78×10^-9 per bp per year, falling within the range of published rates. The mutation rate for Y-chromosomal STRs was 0.0022 per locus per generation, very close to the so-called genealogical rate. The “clan-based” approach to estimating the mutation rate provides a third, middle way between direct farther-to-son comparisons and using archeologically known migrations, whose dates are subject to revision and of uncertain relationship to genetic events.</p></div