TY - JOUR
T1 - Selection for translation efficiency on synonymous polymorphisms in recent human evolution
AU - Waldman, Yedael Y.
AU - Tuller, Tamir
AU - Keinan, Alon
AU - Ruppin, Eytan
PY - 2011
Y1 - 2011
N2 - Synonymous mutations are considered to be "silent" as they do not affect protein sequence. However, different silent codons have different translation efficiency (TE), which raises the question to what extent such mutations are really neutral. We perform the first genome-wide study of natural selection operating on TE in recent human evolution, surveying 13,798 synonymous single nucleotide polymorphisms (SNPs) in 1,198 unrelated individuals from 11 populations. We find evidence for both negative and positive selection on TE, as measured based on differentiation in allele frequencies between populations. Notably, the likelihood of an SNP to be targeted by positive or negative selection is correlated with the magnitude of its effect on the TE of the corresponding protein. Furthermore, negative selection acting against changes in TE is more marked in highly expressed genes, highly interacting proteins, complex members, and regulatory genes. It is also more common in functional regions and in the initial segments of highly expressed genes. Positive selection targeting sites with a large effect on TE is stronger in lowly interacting proteins and in regulatory genes. Similarly, essential genes are enriched for negative TE selection while underrepresented for positive TE selection. Taken together, these results point to the significant role of TE as a selective force operating in humans and hence underscore the importance of considering silent SNPs in interpreting associations with complex human diseases. Testifying to this potential, we describe two synonymous SNPs that may have clinical implications in phenylketonuria and in Best's macular dystrophy due to TE differences between alleles.
AB - Synonymous mutations are considered to be "silent" as they do not affect protein sequence. However, different silent codons have different translation efficiency (TE), which raises the question to what extent such mutations are really neutral. We perform the first genome-wide study of natural selection operating on TE in recent human evolution, surveying 13,798 synonymous single nucleotide polymorphisms (SNPs) in 1,198 unrelated individuals from 11 populations. We find evidence for both negative and positive selection on TE, as measured based on differentiation in allele frequencies between populations. Notably, the likelihood of an SNP to be targeted by positive or negative selection is correlated with the magnitude of its effect on the TE of the corresponding protein. Furthermore, negative selection acting against changes in TE is more marked in highly expressed genes, highly interacting proteins, complex members, and regulatory genes. It is also more common in functional regions and in the initial segments of highly expressed genes. Positive selection targeting sites with a large effect on TE is stronger in lowly interacting proteins and in regulatory genes. Similarly, essential genes are enriched for negative TE selection while underrepresented for positive TE selection. Taken together, these results point to the significant role of TE as a selective force operating in humans and hence underscore the importance of considering silent SNPs in interpreting associations with complex human diseases. Testifying to this potential, we describe two synonymous SNPs that may have clinical implications in phenylketonuria and in Best's macular dystrophy due to TE differences between alleles.
KW - Allele frequency differentiation
KW - Causal variants
KW - Population genetics
KW - SNP
KW - Synonymous mutations
KW - Translation efficiency
UR - http://www.scopus.com/inward/record.url?scp=84856387699&partnerID=8YFLogxK
U2 - 10.1093/gbe/evr076
DO - 10.1093/gbe/evr076
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AN - SCOPUS:84856387699
SN - 1759-6653
VL - 3
SP - 749
EP - 761
JO - Genome Biology and Evolution
JF - Genome Biology and Evolution
IS - 1
ER -