Premature termination codons in modern human genomes

The considerable range of genetic variation in human populations may partly reflect distinctive processes of adaptation to variable environmental conditions. However, the adaptive genomic signatures remain to be completely elucidated. This research explores candidate loci under selection at the population level by characterizing recently arisen premature termination codons (PTCs), some of which indicate a human knockout. From a total of 7595 participants from two population exome projects, 246 PTCs were found where natural selection has resulted in new alleles with a high frequency (from 1% to 96%) of derived alleles and various levels of population differentiation (FST = 0.00139–0.626). The PTC genes formed protein and regulatory networks limited to 15 biological processes or gene families, of which seven categories were previously unreported. PTC mutations have a strong tendency to be introduced into members of the same gene family, even during modern human evolution, although the exact nature of the selection is not fully known. The findings here suggest the ongoing evolutionary plasticity of modern humans at the genetic level and also partly provide insights into common human knockouts.

Note: GO and interactome analyses in Figure 2 were performed using "235" genes. The gene functions were classified "by genes", and thus the gene-by-gene PTC frequency was calculated and used for selection of genes. I assume that, without this criteria, it is difficult to determine which gene is frequently mutated, a gene with PTC with DAF=1.1% or a gene with two PTCs with DAF 0.9%.  Accession number Total  AA  EA  ALL  AFR  AMR  ASN  EUR  ASW  CEU  CHB  CHS  CLM  FIN  GBR  IBS  JPT  LWK  MXL  PUR  TSI    as was previously noted (2), but we cannot detect the any relationship between classification and disappearing genes. The ligands for ORs currently remain unknown due to the redundant nature of the combinatorial code for odorant identity (1). By assigning ligands to ORs, measuring the functional consequences of segregating polymorphisms in vitro and linking in vitro function to human behavior, these data will provide new insights into modern evolution of olfactory perception.

Solute Carrier
The solute-carrier (SLC) gene superfamily encodes membrane-bound transporters (4,5). The SLC superfamily comprises 55 gene families having over 365 putatively functional protein-coding genes (4,5). The gene products act as uniporters, symporters and antiporters, located in plasma cell membranes and organelle membranes (4,5). Transported substrates include amino acids, neurotransmitters, sugars, inorganic cations/anions, bile salts, thyroid hormone, and so on (4,5). The SLC family including five disappearing genes may share the substrates and signaling pathways in common (4,5), and these may have facilitated evolution of SLC family.

Keratin
In this analysis we showed that KRT83 for type II hair keratin (6), six KRTAPs (7,8) and two FLGs (9,10) have reduced in the numbers very recently in the human evolution although an expanded KRTAP gene repertoire is found even among some primates. Keratins and their related genes are major components of the hair fiber, which is unique structure found on all mammals (6-10). High-frequency PTCs in Keratin, KRTAPs and FLGs could potentially explain the differing hair features of human lineages and the thinning of human body hair. And clothing, along with large climate change or modern technology may be a one of the primary driving force of hair-related gene evolution and made the insulating properties of body hair obsolete.

Zinc finger
The human genome encodes over 700 zinc finger (ZNF) genes, which perform key roles in transcription process (11). The dramatic increase in the number of ZNF genes are observed from yeast to Drosophila, to Xenopus and to humans and gene duplication has facilitated the expansion of this family in eukaryotic lineages (12).
Recent study of adaptive evolution among ZNF paralogs using dN/dS analysis shows that a major component of the selective pressure acting on ZNF genes has been positive selection to change their DNA-binding specificity (12). The reduction of number in ZNF genes we detected may be a sequence of ZNF evolution and thus driver for eukaryotic evolution.

Taste
Taste is a primitive sense that helps detect and distinguish key dietary components along with olfaction (13). The sensation of taste is classified into five prototypical categories: sweet, bitter, sour, umami, and salty (13). In addition recent studies raise the possibility of an additional sixth and seventh taste modality devoted to the perception of fats (14) and calcium (15). We have recently showed that modern humans may have been losing their taste receptors and molecular evolutionary rates of sour and bitter receptors were considerably higher in humans than those of sweet, umami, and salty receptors in contrast to other carnivorous mammals (16). Much is still unknown about relationships among their genetic variants, dietary choices, and the signal transmission pathways. Further biochemical studies are required to clarify the relationship between modern human's taste and genetic variants.

Spermatogenesis
Spermatogenesis is a long and complex process that, despite the shared overall goal of forming the male gamete, displays striking amounts of interspecific diversity (17). The product of many genes play important roles in various aspects of spermatogenesis (18). Spermatogenesis-associated (SPATA) family we detected is necessary for the formation of the sperm acrosome (19,20). DNAH family is involved in sperm motility and part of the sperm flagella assembly (21). A greater increase in their rate of evolution is observed relative to genes expressed in other tissues and stronger sexual selection pressure acting on these genes (17). The reduced number of genes associated with spermatogenesis have likely followed this tendency even during human evolution.

Drug metabolism
Recent pharmacogenomic researches have revealed extensive variations in drug-metabolizing capacity among individuals (22,23). The main indexes for this variation in drug metabolism are variability of UDP-glucuronosyltransferase and Cytochrome P450 genes, which have been proven to be highly polymorphic (22,23,24).
Such polymorphisms have been shown to be of importance for causing adverse effects or lack of therapeutic efficacy (22,23,24). Our results raise the possibility that modern humans might have been losing their drug-metabolizing ability. Modern life's evolutionary pressures, such as improvement of diets, irritants and toxicant, may be hastening the human CYP evolution.

RNA virus
The endogenous viral elements (EVE) are DNA sequences derived from retrovirus or non-retrovirus (25,26). More than 10% of the human genome is made up of these elements (25,26). Despite recent advances in studies of EVEs, their function is still unknown. Here we detected four EVEs: EBLN2 is non-retroviral origin, and ERVMER34-1, ERV3-1 and HHLA3 are retroviral ones.

Ligand for NGK2D
Six ULBP/RAET (UL16-binding protein, also known as retinoic acid early transcript) genes encode ligands of the activating immunoreceptor NKG2D and are associated with NK-cell activation (27,28). Out of six genes, ULBP6/RAET1L, ULBP4/RAET1E and ULBP3/RAET1N are frequently mutated. It is expected that there is a functional redundancy among a set of NKG2D ligands.
Interferon defense receptors raises the question of whether there is an evolutionary advantage to having these genetic variants. One rational explanation for this is that these mutations provides protection against autoimmune disease as one of evolutionary pressures. This hypothesis is supported by the previous report that TLR5 PTC mutation leads to resistance to systemic lupus erythematosus (SLE) (36). To make a negative interpretation we guess that modern humans may have physically weaker and more susceptible to pathogens.

Other gene family
The POTE family genes encode a highly homologous group of primate-specific proteins that contain ankyrin repeats and coiled coil domains and is induced in many cancers (e.g. prostate cancer) (37,38). The MAGE (melanoma-associated antigen) gene family was originally identified as "a melanoma antigen" and share a homologous MAGE conserved domain located close to the C-terminal (39,40). The acyl-CoA synthetase medium-chain (ACSM) family encode for enzymes catalyzing the activation of medium-chain length fatty acids (41,42) and is associated with plasma high-density lipoprotein cholesterol levels (42). Although the function of these family is largely unknown, we conclude that PTC mutations have a strong tendency to be introduced to the members of the same gene family even during human evolution.