ORCID Profile
0000-0003-3425-6998
Current Organisation
University of Michigan
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Publisher: Springer Science and Business Media LLC
Date: 30-09-2015
DOI: 10.1038/NATURE15394
Publisher: Springer Science and Business Media LLC
Date: 11-12-1994
DOI: 10.1038/NATURE15393
Publisher: Springer Science and Business Media LLC
Date: 12-06-2011
DOI: 10.1038/NG.862
Publisher: Springer Science and Business Media LLC
Date: 31-10-2012
DOI: 10.1038/NATURE11632
Publisher: Cold Spring Harbor Laboratory
Date: 11-03-2013
Abstract: Short insertions and deletions (indels) are the second most abundant form of human genetic variation, but our understanding of their origins and functional effects lags behind that of other types of variants. Using population-scale sequencing, we have identified a high-quality set of 1.6 million indels from 179 in iduals representing three erse human populations. We show that rates of indel mutagenesis are highly heterogeneous, with 43%–48% of indels occurring in 4.03% of the genome, whereas in the remaining 96% their prevalence is 16 times lower than SNPs. Polymerase slippage can explain upwards of three-fourths of all indels, with the remainder being mostly simple deletions in complex sequence. However, insertions do occur and are significantly associated with pseudo-palindromic sequence features compatible with the fork stalling and template switching (FoSTeS) mechanism more commonly associated with large structural variations. We introduce a quantitative model of polymerase slippage, which enables us to identify indel-hypermutagenic protein-coding genes, some of which are associated with recurrent mutations leading to disease. Accounting for mutational rate heterogeneity due to sequence context, we find that indels across functional sequence are generally subject to stronger purifying selection than SNPs. We find that indel length modulates selection strength, and that indels affecting multiple functionally constrained nucleotides undergo stronger purifying selection. We further find that indels are enriched in associations with gene expression and find evidence for a contribution of nonsense-mediated decay. Finally, we show that indels can be integrated in existing genome-wide association studies (GWAS) although we do not find direct evidence that potentially causal protein-coding indels are enriched with associations to known disease-associated SNPs, our findings suggest that the causal variant underlying some of these associations may be indels.
Publisher: Elsevier BV
Date: 12-2012
Publisher: American Association for the Advancement of Science (AAAS)
Date: 17-02-2012
Abstract: Identifying genes that give rise to diseases is one of the major goals of sequencing human genomes. However, putative loss-of-function genes, which are often some of the first identified targets of genome and exome sequencing, have often turned out to be sequencing errors rather than true genetic variants. In order to identify the true scope of loss-of-function genes within the human genome, MacArthur et al. (p. 823 see the Perspective by Quintana-Murci ) extensively validated the genomes from the 1000 Genomes Project, as well as an additional European in idual, and found that the average person has about 100 true loss-of-function alleles of which approximately 20 have two copies within an in idual. Because many known disease-causing genes were identified in “normal” in iduals, the process of clinical sequencing needs to reassess how to identify likely causative alleles.
No related grants have been discovered for Ryan Mills.