Dataset Information

No evidence that selection has been less effective at removing deleterious mutations in Europeans than in Africans.

ABSTRACT: Non-African populations have experienced size reductions in the time since their split from West Africans, leading to the hypothesis that natural selection to remove weakly deleterious mutations has been less effective in the history of non-Africans. To test this hypothesis, we measured the per-genome accumulation of nonsynonymous substitutions across diverse pairs of populations. We find no evidence for a higher load of deleterious mutations in non-Africans. However, we detect significant differences among more divergent populations, as archaic Denisovans have accumulated nonsynonymous mutations faster than either modern humans or Neanderthals. To reconcile these findings with patterns that have been interpreted as evidence of the less effective removal of deleterious mutations in non-Africans than in West Africans, we use simulations to show that the observed patterns are not likely to reflect changes in the effectiveness of selection after the populations split but are instead likely to be driven by other population genetic factors.

SUBMITTER: Do R

PROVIDER: S-EPMC4310772 | biostudies-literature | 2015 Feb

REPOSITORIES: biostudies-literature

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No evidence that selection has been less effective at removing deleterious mutations in Europeans than in Africans.

Do Ron R Balick Daniel D Li Heng H Adzhubei Ivan I Sunyaev Shamil S Reich David D

Nature genetics 20150112 2

Non-African populations have experienced size reductions in the time since their split from West Africans, leading to the hypothesis that natural selection to remove weakly deleterious mutations has been less effective in the history of non-Africans. To test this hypothesis, we measured the per-genome accumulation of nonsynonymous substitutions across diverse pairs of populations. We find no evidence for a higher load of deleterious mutations in non-Africans. However, we detect significant diffe ...[more]

PMID: 25581429

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Project description:Background and objectivesAmyotrophic lateral sclerosis (ALS) is a degenerative condition of the brain and spinal cord in which protein-coding variants in known ALS disease genes explain a minority of sporadic cases. There is a growing interest in the role of noncoding structural variants (SVs) as ALS risk variants or genetic modifiers of ALS phenotype. In small European samples, specific short SV alleles in noncoding regulatory regions of SCAF4, SQSTM1, and STMN2 have been reported to be associated with ALS, and several groups have investigated the possible role of SMN1/SMN2 gene copy numbers in ALS susceptibility and clinical severity.MethodsUsing short-read whole genome sequencing (WGS) data, we investigated putative ALS-susceptibility SCAF4 (3'UTR poly-T repeat), SQSTM1 (intron 5 AAAC insertion), and STMN2 (intron 3 CA repeat) alleles in African ancestry patients with ALS and described the architecture of the SMN1/SMN2 gene region. South African cases with ALS (n = 114) were compared with ancestry-matched controls (n = 150), 1000 Genomes Project samples (n = 2,336), and H3Africa Genotyping Chip Project samples (n = 347).ResultsThere was no association with previously reported SCAF4 poly-T repeat, SQSTM1 AAAC insertion, and long STMN2 CA alleles with ALS risk in South Africans (p > 0.2). Similarly, SMN1 and SMN2 gene copy numbers did not differ between South Africans with ALS and matched population controls (p > 0.9). Notably, 20% of the African samples in this study had no SMN2 gene copies, which is a higher frequency than that reported in Europeans (approximately 7%).DiscussionWe did not replicate the reported association of SCAF4, SQSTM1, and STMN2 short SVs with ALS in a small South African sample. In addition, we found no link between SMN1 and SMN2 copy numbers and susceptibility to ALS in this South African sample, which is similar to the conclusion of a recent meta-analysis of European studies. However, the SMN gene region findings in Africans replicate previous results from East and West Africa and highlight the importance of including diverse population groups in disease gene discovery efforts. The clinically relevant differences in the SMN gene architecture between African and non-African populations may affect the effectiveness of targeted SMN2 gene therapy for related diseases such as spinal muscular atrophy.

Dataset Information

No evidence that selection has been less effective at removing deleterious mutations in Europeans than in Africans.

Publications

No evidence that selection has been less effective at removing deleterious mutations in Europeans than in Africans.

Similar Datasets

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