The overdue promise of short tandem repeat variation for heritability

Press, Maximilian O.; Carlson, Keisha D.; Queitsch, Christine

doi:10.1016/j.tig.2014.07.008

Cited by 103 publications

(108 citation statements)

References 98 publications

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“…Interestingly, we found that loci with dinucleotide motifs show relatively weak LD with SNPs, suggesting that GWAS studies with SNP arrays are prone to miss causal STR loci. Given the theoretical potential of STRs to contribute to phenotypic variance on one hand and their weaker LD to tagging SNPs on the other hand, one intriguing possibility is that STRs contribute to the missing heritability phenomenon of complex traits (Manolio et al 2009;Press et al 2014). Our hope is that this catalog can be a reference point to test this hypothesis in future studies.…”

Section: Discussionmentioning

confidence: 99%

The landscape of human STR variation

et al. 2014

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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.

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Section: Discussionmentioning

confidence: 99%

The landscape of human STR variation

et al. 2014

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“…The combination of the two approaches will yield much reliable and important information regarding repeat variation in natural populations. Such TR genotyping from wholegenome sequencing data will have a profound impact on many fields, from conservation genetics to forensics, and on elucidating the role of TRs in complex trait heritability (Press et al 2014).…”

Section: Tandem Repeats Increase Expression Divergencementioning

confidence: 99%

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

et al. 2015

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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.

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“…The most hypermutable microsatellites tend to have a high A/T content 26 and have a large number of repeated subunits. Because long microsatellites have a 27 tendency to contract more often than they expand [12], microsatellites undergo a 28 lifecycle in which they are "born" and "die" in the genome over evolutionary time [8,13]. 29 Tandem repeats composed of subunits greater than nine base-pairs are called 30 minisatellites.…”

mentioning

confidence: 99%

“…Tandem repeats have been hypothesized to be partially responsible 55 for missing heritability [18,27], and may also be partially responsible for some of the 56 still-missing heritability. Due to their high mutability, tandem repeats can mutate away 57 from linkage with surrounding SNPs, and therefore SNP association studies are not 58 expected to pick up all of the heritability caused by hypermutable variants.…”

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confidence: 99%

Linkage disequilibrium between single nucleotide polymorphisms and hypermutable loci

Sawaya

Jones

2015

Preprint

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Some diseases are caused by genetic loci with a high rate of change, and heritability in complex traits is likely to be partially caused by variation at these loci. These hypermutable elements, such as tandem repeats, change at rates that are orders of magnitude higher than the rates at which most single nucleotides mutate. However, single nucleotide polymorphisms, or SNPs, are currently the primary focus of genetic studies of human disease. Here we quantify the degree to which SNPs are correlated with hypermutable loci by examining a range of mutation rates. We use established population genetics theory to relate mutation rates to recombination rates and compare the theoretical predictions to simulations. Both simulations and theory agree that, at the highest mutation rates, almost all correlation is lost between a hypermutable locus and surrounding SNPs. The theoretical predictions break down as the mutation rate increases, and consequently differ widely from the simulated results. The simulation results suggest that some correlation remains between SNPs and hypermutable loci when mutation rates are on the lower end of the mutation spectrum. Consequently, in some cases SNPs can tag variation caused by some hypermutable loci. We also examine the linkage between SNPs and other SNPs and uncover ways in which the linkage disequilibrium of rare SNPs differs from that of hypermutable loci.

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The overdue promise of short tandem repeat variation for heritability

Cited by 103 publications

References 98 publications

The landscape of human STR variation

The landscape of human STR variation

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

Linkage disequilibrium between single nucleotide polymorphisms and hypermutable loci

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