Loss of gene function and evolution of human phenotypes
Loss of gene function and evolution of human phenotypes
BMB Reports. 2015. Jul, 48(7): 373-379
Copyright © 2015, Korean Society for Biochemistry and Molecular Biology
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  • Received : April 11, 2015
  • Published : July 31, 2015
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Hye Ji, Oh
Dongjin, Choi
Chul Jun, Goh
Yoonsoo, Hahn

Humans have acquired many distinct evolutionary traits after the human-chimpanzee divergence. These phenotypes have resulted from genetic changes that occurred in the human genome and were retained by natural selection. Comparative primate genome analyses reveal that loss-of-function mutations are common in the human genome. Some of these gene inactivation events were revealed to be associated with the emergence of advantageous phenotypes and were therefore positively selected and fixed in modern humans (the “less-ismore” hypothesis). Representative cases of human gene inactivation and their functional implications are presented in this review. Functional studies of additional inactive genes will provide insight into the molecular mechanisms underlying acquisition of various human-specific traits. [BMB Reports 2015; 48(7): 373-379]
Humans diverged from the chimpanzee lineage approximately 5-7 million years ago (MYA) (1 - 3) . Humans have many specific traits compared with closely related apes that must have resulted from genetic modifications acquired during evolution (2) . For example, the human FOXP2 gene shows accelerated amino acid sequence substitutions during human evolution and may have played an important role in language and speech evolution by altering transcription of genes responsible for the development of the central nervous system (4 , 5) . Human accelerated region 1 noncoding RNA shows accelerated nucleotide sequence substitutions in the human lineage and is highly expressed in human neocortex, possibly playing a role in the evolution of human brain development (6 , 7) .
Sequence comparisons of complete genomes of human and related primates has enabled the large-scale identification of genetic modifications in the human lineage, including accelerated sequence substitutions, novel transcript isoforms, and acquisitions of posttranslational modification sites (6 , 8 - 14) . Molecular functions of most of these changes and their associated human-specific phenotypes are not yet established.
According to the “less-is-more” hypothesis, loss of gene function can be implicated in the evolution of human-specific traits (15) . In general, loss of gene function by disrupting mutations would be deleterious to individual fitness, and purifying selection would remove the mutant allele from the population. However, environmental or behavioral changes of an organism may relax the selection constraints on a gene, which could then accumulate disrupted mutations without loss of fitness. Under certain circumstances, the absence of intact proteins can be more advantageous, and pseudogenizing mutations might then be favored and increase in frequency, eventually becoming fixed in a species.
In humans, one of the examples that potentially supports the adaptive pseudogenization hypothesis is the MYH16 gene, for which inactivation has been suggested to be involved in human brain expansion (16) . The loss of human CMAH gene function appears to be associated with the evolution of susceptibilities to malaria or typhoid toxins (17 , 18) . Loss of regulatory elements, as evidenced by hCONDEL.569 and HACNS1, can dramatically change expression patterns of nearby genes and confer human-specific anatomical traits (19 , 20) . In addition, a large number of human-specific gene losses have been identified thus far using comparative genomics studies (21 - 27) . Here, we review representative cases of human gene inactivation and their functional implications.
The CMAH gene encodes for cytidine monophosphate-N-acetylneuraminic acid hydroxylase, which is an enzyme responsible for the biosynthesis of N-glycolylneuraminic acid (Neu5Gc), a hydroxylated form of the common sialic acid N-acetylneuraminic acid (Neu5Ac) (28) . Sequence comparisons have shown that there is a 92-bp deletion in the coding region of the human gene, while the chimpanzee gene is intact, indicating the human gene was inactivated after the human-chimpanzee divergence (29) . The absence of active CMAH enzyme in humans resulted in differences in the glycan composition between humans and other primates: human sialoglycans terminate in Neu5Ac, whereas those of other primates and most other mammals terminate in Neu5Gc (30) . The human-specific pseudogenization of the CMAH gene occurred approximately 3 MYA through an Alu-mediated exon deletion (31 - 33) .
The phenotypic consequences of the loss of CMAH are of great interest and have been studied extensively. Initially, it was proposed that the loss of Neu5Gc moiety might be associated with the brain expansion of humans (32) . However, a study has suggested that the differences in sialoglycan might instead be associated with the differences in malaria susceptibilities between humans and chimpanzees (34) . Plasmodium falciparum is the global cause of malaria mortality in humans; however, it does not cause severe infection in chimpanzees. P. reichenowi , which is the closest relative of P. falciparum , infects chimpanzees and gorillas but not humans.
To explain this interesting relationship, the inactivation of the CMAH gene in early humans and the subsequent evolution of the parasite has been proposed (17 , 35) . Inactivation of the CMAH gene rendered human ancestors incapable of synthesizing Neu5Gc from Neu5Ac. Abolishment of Neu5Gc from human erythrocytes might make humans resistant to P. reichenowi , which strongly prefers Neu5Gc. The resistance to P. reichenowi malaria could have been advantageous to human ancestors, and the inactive CMAH gene was fixed in the human lineage. More recently, however, a lineage of P. falciparum that is widely present in African great apes, especially in western gorillas, might have cross-infected humans (36) . The strong preference for the overabundant Neu5Ac in human red blood cells might be responsible for the cross-species transmission of P. falciparum malaria and its emergence as the deadliest human pathogen (17 , 34) .
Glycans that terminate in Neu5Ac are associated with the host specificity of other exclusively human pathogens, such as Salmonella Typhi and human influenza A virus (IAV) (18 , 37) . The typhoid toxin selectively binds to Neu5Ac-terminated glycans and displays selective toxicity toward cells expressing them. Ferrets have also lost the CMAH gene through a nine-exon deletion, which is shared by the Pinnipedia and Musteloidia members of Carnivora, and they exhibit susceptibility to human-adapted IAV strains. Thus, the evolution of resistance to a certain pathogen through CMAH gene inactivation and subsequent development of susceptibility to other parasites is a good example of the evolutionary arms race between hosts and parasites (35 , 38) .
The MYH16 gene encodes a sarcomeric myosin heavy chain, which is a major component of masticatory (jaw-closing) muscles (39) . The human MYH16 gene is a pseudogene and does not produce functional protein due to a two-nucleotide deletion in exon 18. This deletion occurred in the human lineage after the human-chimpanzee divergence and has been fixed in modern humans (16) . The loss of the MYH16 gene product in humans has been proposed to be associated with a marked reduction in masticatory muscle mass, which might have allowed humans to have bigger brains (16 , 40 , 41) . Initially, this frameshift mutation in MYH16 was estimated to have appeared approximately 2.4 MYA, predating the appearance of Homo erectus/ergaster , which had a relatively gracile masticatory apparatus. The age of the inactivating mutation appears to support the idea that the loss of the MYH16 gene could be a crucial step for the enhanced encephalization of humans (16) .
However, a more comprehensive analysis revealed that the human-specific deletion might have occurred approximately 5.3 MYA, which significantly precedes the first appearance of the genus Homo in the fossil record (42) . The study also claimed that inactivation of the MYH16 gene would have had little contribution to the expansion of the brain, as the majority of brain growth in humans occurs long before the development of the masticatory musculature (43) . Another study has indicated that, although humans have relatively small jaws and jaw muscles compared with those of closely related great apes, the human masticatory apparatus is highly efficient and can produce relatively high bite forces using low muscle forces (44) .
It is possible that a dietary shift, perhaps to consuming softer foods, might have permitted smaller jaws in early humans, which led to a lower dependency on the MYH16 gene product (45) . It is also likely that human ancestors evolved smaller jaws and chewing muscles without losing overall masticatory function. As a result, the MYH16 gene might have simply become extraneous, and under relaxed selection pressure, the gene accumulated disruptive mutations. Although the pseudogenization event of the MYH16 gene might not have directly driven encephalization, it is a compelling example of the association between gene inactivation and the acquisition of human-specific phenotypes.
There are five major taste sensations in humans and most other vertebrates: salty, sour, sweet, umami (savory), and bitter. Each of these tastes is perceived by distinct sets of taste receptors (46) . In various mammals, taste receptor genes are often pseudogenized as they adapt to different dietary habits and life styles. For example, cats are not able to detect the sweetness of sugars because of their loss of functional sweet receptors, likely a result of their carnivorous behavior (47) . Giant pandas lack a functional umami taste receptor gene; the inactivation of which was reported to coincide with their dietary shift to bamboo (48) . Bottlenose dolphins lost receptors for the three basic tastes, sweet, bitter, and umami, most likely as a result of swallowing food whole, without chewing (49) .
Bitter taste sensation is mediated by type 2 taste receptors (TAS2Rs) and is usually associated with detection and avoidance of toxic chemical substances or putrid food (46) . Sequence comparison of TAS2R genes among mammals revealed that two of them, TAS2R62 and TAS2R64 , are pseudogenes in humans, which became inactivated due to nonsense and/or frameshift mutations after the human-chimpanzee divergence and fixed in the modern human population (50 , 51) . These two pseudogenes are shared with other archaic humans, Neanderthals and Denisovans, indicating their ancient origins (52) . TAS2R genes with an intact coding region also show relaxation of selective constraints, implying that the bitter taste sensation is generally reduced in the human lineage in comparison with other mammals (53) .
Loss and/or relaxed selection of TAS2R genes may be associated with the dietary shift of ancestral humans (52) . Human ancestors consumed more starch-rich tuberous roots such as yams, which generally tasted bitter. Extra calories obtained from these bitter root vegetables may have allowed humans to develop bigger brains. Eventually, humans learned to cook in order to remove bitter substances, which might have further reduced selection pressure on bitter taste receptor genes. Therefore, loss and/or relaxed selection of TAS2R genes might be deeply interwoven with the evolution of human dietary habits.
Olfaction, or the perception of smell, is a crucial sense for animals and plays an important role in avoiding predators, searching for foods, and recognizing the opposite sex. Olfactory receptors (ORs) in the olfactory epithelium are responsible for the detection and discrimination of various odorants (54) . The olfactory perception capabilities of humans, other apes, and Old World monkeys (OWMs) are generally considered to be significantly diminished when compared with other mammals, based on observations that these species have relatively small olfactory apparatuses and high number of OR pseudogenes (55 - 57) . It has been proposed that humans and other catarrhines (OWMs and apes) have become more dependent on vision rather than olfaction, which created a relaxed selection pressure on OR genes (57) .
However, various studies have suggested that there is no direct link between the evolution of trichromatic color vision and the degeneration of OR genes in catarrhines (58 , 59) . Another study claimed that humans are capable of distinguishing between more than 1 trillion olfactory stimuli (60) . Recently, this estimation has been questioned and should be scrutinized by further studies (61) .
Interestingly, some olfaction-related genes other than OR genes are inactivated in humans. For example, transient receptor potential cation channel, subfamily C, member 2 (TRPC2), which is required for pheromone sensing, is a pseudogene in humans (62 , 63) . A comparative genomics study of primates revealed that the TRPC2 gene is a pseudogene not only in humans but also in other catarrhines, indicating that the gene became inactivated in a common ancestor of OWMs and apes (64) . It has been speculated that the development of trichromatic color vision might have led to a reduced dependency on chemosensory communication for mediating a variety of social behaviors, although humans seem to still rely on chemosignals for certain interactions (65) .
The MOXD2 gene, which encodes a highly conserved monooxygenase DBH-like 2 protein in vertebrates, is another inactive gene that is proposed to be involved in olfaction in humans (21) . The human MOXD2 gene has an exon-deletion mutation, which occurred after the human-chimpanzee divergence. The mouse ortholog Moxd2 gene has been reported to be highly expressed in olfactory epithelium, implying that vertebrate MOXD2 could be involved in olfactory function (66) . MOXD2 and its paralogs, MOXD1 and DBH, belong to the copper type II, ascorbate-dependent monooxygenase family. DBH is a dopamine β-hydroxylase, which converts dopamine to norepinephrine (noradrenaline) in the synaptic vesicles of postganglionic sympathetic neurons and for which deficiency or polymorphism is associated with various neuropsychiatric disorders (67 - 69) . Vertebrate MOXD2 might also be involved in metabolism of neurotransmitters, potentially during transduction of olfactory stimuli.
The MOXD2 gene is also inactive in other apes: orangutans have multiple nonsense mutations and gibbons do not have the gene due to a genomic deletion that occurred in a common ancestor of all contemporary gibbons (21 , 70) . The gorilla gene shows an elevated non-synonymous substitution rate/synonymous substitution rate ratio, perhaps because its selection pressure has been recently relaxed, while the chimpanzee gene appears to be under purifying selection. Therefore, the loss of MOXD2 enzyme function might be associated with the reduced olfactory capabilities of humans and other apes. However, it remains uncertain whether this gene inactivation caused the diminished olfaction or the reduced dependency on olfaction led to relaxed selection pressure on the gene (21) .
Interestingly, MOXD2 gene inactivation also occurred in another mammalian clade, the Cetacea (70) . The dolphin and whale MOXD2 genes underwent a broad range of disruptive mutations, including nonsense, frameshift, and complete deletion. In whales, the TRPC2 gene is also a pseudogene, and many OR genes are not functional (71 - 73) . The degeneration of these genes may coincide with the evolution of a fully aquatic lifestyle and highly sophisticated vocal communication and/or echolocation. Therefore, inactivation of olfaction-related genes of humans and other organisms may be a remarkable molecular signature of adaptive evolution to habitat shifts and/or sociobehavioral changes.
Sequence polymorphisms resulting in loss of function of a derived allele are frequently observed in the human population, indicating that gene inactivation events are rather common (24 , 26 , 74 - 76) . Population genetic studies have demonstrated that inactive allele frequencies range from rare to common, with some being nearly fixed (24 , 26) . Many of these inactive alleles have been reported to be associated with beneficial phenotypes in the individuals harboring them (75) . Examples include: polymorphic pseudogenes in some TAS2R genes for bitter taste (51) , a 32-bp deletion allele of the CCR5 gene that is found in relatively high frequency in Europeans (77) , a nonsense allele of the CASP12 gene that is rare in Africans but very common in non-Africans (78 , 79) , and a nonsense allele of the ACTN3 gene that is commonly detected in various human populations (80) .
Humans generally have 26 intact TAS2R genes for bitter taste sensation (51) . TAS2R genes exhibit a high level of polymorphisms among human individuals, including non-synonymous substitutions and copy-number variations. Interestingly, some polymorphisms involve loss-of-function mutations; there are polymorphic pseudogenes in TAS2R2 , TAS2R7 , TAS2R45 , and TAS2R46 as well as polymorphic whole-gene deletions in TAS2R43 and TAS2R45 (51 , 53 , 81 - 83) . Loss of a specific TAS2R gene is involved in individual-specific phenotypes in bitter taste sensation. For example, the bitter taste receptor encoded by the TAS2R43 gene responds to the artificial sweetener saccharin and contributes to the bitter aftertaste of saccharine and other related sweeteners (84) . Lack of the TAS2R43 gene renders affected individuals to be insensitive to the bitterness of saccharine and other natural plant compounds, including aloin and aristolochic acid (83) .
The human CCR5 gene encodes for C-C chemokine receptor type 5 (alsoknownasCD195), which is a G-protein coupled receptor on the cell surface of white blood cells and acts as a receptor for chemokines (85) . Human immunodeficiency viruses (HIVs) initially bind CCR5 proteins to enter and infect mucosal CD4 + T cells, which eventually may cause acquired immune deficiency syndrome (AIDS) (86 , 87) . A 32-bp deletion mutation in the CCR5 gene, referred to as the CCR5-Δ32 allele, is almost exclusively found in approximately 5%-14% of the European population and their descendants (77) . The mutant allele produces defective proteins that cannot be detected on the cell surface. This lack of CCR5 protein on the cell surface protects individuals homozygous for the CCR5-Δ32 allele from HIV infection (88) . Because the frequency of this pseudogene allele is relatively high in Europeans, it was initially suggested that this allele appeared recently (approximately 1,000 years ago) and has undergone positive selection (77) . However, a detailed study of the allele age and pattern of genetic variation revealed that the CCR5-Δ32 allele may have arisen more than 5,000 years ago and was selected for another reason or neutrally evolved, indicating that its resistance to HIV was pre-adaptive (89) . Nevertheless, the resistance to HIVs and protection against AIDS as a result of CCR5 gene inactivation suggest that the CCR5 protein is a promising therapeutic target for preventing the spread of HIV [90 , 91] .
The CASP12 gene encodes caspase 12, which belongs to a family of cysteine proteases that cleaves their substrates at C-terminal aspartic acid residues (92) . There is a nonsense polymorphism in the human CASP12 gene, namely, a stop codon in exon 4 induces premature termination (79 , 93) . The inactive allele is very common in non-Africans, but rare in Africans. Intact full-length caspase 12 attenuates the inflammatory and innate immune responses to endotoxins, which can result in a severe septic response (79) . Thus, the nonsense allele is advantageous as it confers resistance to severe sepsis, and it could have recently undergone positive selection in non-Africans (25 , 78) . The inactive allele appears to have originated in Africa and was initially neutral or approximately neutral. As human population size and density increased, individuals may have experienced more infectious diseases, for which the inactive allele was highly advantageous as a result of sepsis resistance (78) . The human CASP12 gene is another example of a pre-adaptive gene inactivation and subsequent positive selection.
The human ACTN3 gene encodes α-actinin-3, an actinbinding protein found in skeletal muscle (94) . ACTN3 proteins are a major structural component of Z lines and regulate the function of fast twitch (type II) muscle fibers, which underlie forceful and rapid muscle contraction during athletic activities such as sprinting (95) . There is a nonsense polymorphism R577X in exon 16 of the ACTN3 gene (80 , 95) . This mutation results in undetectable ACTN3 protein in skeletal muscle. Interestingly, the ACTN3 genotype was suggested to be associated with human elite athletic performance; the 577X allele is associated with endurance, while the 577R allele is associated with sprinting and strength performance (96 - 98) . The high frequency of the nonsense allele in human populations could have resulted from positive selection for improved endurance-running capabilities. This might have bestowed human ancestors increased opportunities for successful scavenging and/or persistence hunting (99 - 101) .
Studies of human genomes have revealed a large number of loss-of-function mutations in humans that are polymorphic or fixed in populations. For example, a study on the genomes of Icelanders revealed a total of 6,795 autosomal loss-of-function alleles that are affected by nonsense or insertion/deletion mutations in 4,924 genes (24 , 102) . Some inactive alleles were found to be shared with archaic humans such as Neanderthals and are thought to be acquired by introgression (102) . These loss-of-function mutations may contribute to the phenotypic variety of modern humans and could act as sources for adaptive evolution during various environmental changes (76) .
The emergence of loss-of-function mutations and their subsequent expansion in modern humans indicate that gene inactivation is one of the mechanisms that confer novel advantageous phenotypes. A large number of gene inactivation events have been identified thus far in the human genome. Several of these exhibited strong association with beneficial traits. However, many have been neglected since these genes are nonfunctional pseudogenes in humans. Molecular functional studies of these genes in model organisms will provide clues about the molecular mechanisms for the emergence of human-specific phenotypes.
This study was supported by the National Research Foundation of Korea (NRF) grant (NRF-2012R1A1B3001513) funded by the Ministry of Education, Science and Technology, Republic of Korea.
Chen FC , Li WH (2001) Genomic divergences between humans and other hominoids and the effective population size of the common ancestor of humans and chimpanzees. Am J Hum Genet 68 444 - 456    DOI : 10.1086/318206
Varki A , Altheide TK (2005) Comparing the human and chimpanzee genomes: searching for needles in a haystack. Genome Res 15 1746 - 1758    DOI : 10.1101/gr.3737405
Patterson N , Richter DJ , Gnerre S , Lander ES , Reich D (2006) Genetic evidence for complex speciation of humans and chimpanzees. Nature 441 1103 - 1108    DOI : 10.1038/nature04789
Enard W , Przeworski M , Fisher SE (2002) Molecular evolution of FOXP2, a gene involved in speech and language. Nature 418 869 - 872    DOI : 10.1038/nature01025
Konopka G , Bomar JM , Winden K (2009) Humanspecific transcriptional regulation of CNS development genes by FOXP2. Nature 462 213 - 217    DOI : 10.1038/nature08549
Pollard KS , Salama SR , Lambert N (2006) An RNA gene expressed during cortical development evolved rapidly in humans. Nature 443 167 - 172    DOI : 10.1038/nature05113
Beniaminov A , Westhof E , Krol A (2008) Distinctive structures between chimpanzee and human in a brain noncoding RNA. RNA 14 1270 - 1275    DOI : 10.1261/rna.1054608
Kim DS , Hahn Y (2011) Identification of human-specific transcript variants induced by DNA insertions in the human genome. Bioinformatics 27 14 - 21    DOI : 10.1093/bioinformatics/btq612
Kim DS , Hahn Y 2011 Identification of novel phosphorylation modification sites in human proteins that originated after the human-chimpanzee divergence. Bioinformatics 27 2494 - 2501
Kim DS , Hahn Y (2012) Gains of ubiquitylation sites in highly conserved proteins in the human lineage. BMC Bioinformatics 13 306 -    DOI : 10.1186/1471-2105-13-306
Kim DS , Hahn Y (2012) Human-specific protein isoforms produced by novel splice sites in the human genome after the human-chimpanzee divergence. BMC Bioinformatics 13 299 -    DOI : 10.1186/1471-2105-13-299
Kim DS , Hahn Y (2015) The acquisition of novel N-glycosylation sites in conserved proteins during human evolution. BMC Bioinformatics 16 29 -    DOI : 10.1186/s12859-015-0468-5
Prabhakar S , Visel A , Akiyama JA (2008) Humanspecific gain of function in a developmental enhancer. Science 321 1346 - 1350    DOI : 10.1126/science.1159974
Rogers J , Gibbs RA (2014) Comparative primate genomics: emerging patterns of genome content and dynamics. Nat Rev Genet 15 347 - 359    DOI : 10.1038/nrg3707
Olson MV (1999) When less is more: gene loss as an engine of evolutionary change. Am J Hum Genet 64 18 - 23    DOI : 10.1086/302219
Stedman HH , Kozyak BW , Nelson A (2004) Myosin gene mutation correlates with anatomical changes in the human lineage. Nature 428 415 - 418    DOI : 10.1038/nature02358
Rich SM , Leendertz FH , Xu G (2009) The origin of malignant malaria. Proc Natl Acad Sci U S A 106 14902 - 14907    DOI : 10.1073/pnas.0907740106
Deng L , Song J , Gao X (2014) Host adaptation of a bacterial toxin from the human pathogen Salmonella Typhi. Cell 159 1290 - 1299    DOI : 10.1016/j.cell.2014.10.057
McLean CY , Reno PL , Pollen AA (2011) Humanspecific loss of regulatory DNA and the evolution of human-specific traits. Nature 471 216 - 219    DOI : 10.1038/nature09774
Sumiyama K , Saitou N (2011) Loss-of-function mutation in a repressor module of human-specifically activated enhancer HACNS1. Mol Biol Evol 28 3005 - 3007    DOI : 10.1093/molbev/msr231
Hahn Y , Jeong S , Lee B (2007) Inactivation of MOXD2 and S100A15A by exon deletion during human evolution. Mol Biol Evol 24 2203 - 2212    DOI : 10.1093/molbev/msm146
Hahn Y , Lee B (2005) Identification of nine humanspecific frameshift mutations by comparative analysis of the human and the chimpanzee genome sequences. Bioinformatics 21 (Suppl 1) i186 - 194    DOI : 10.1093/bioinformatics/bti1000
Hahn Y , Lee B (2006) Human-specific nonsense mutations identified by genome sequence comparisons. Hum Genet 119 169 - 178    DOI : 10.1007/s00439-005-0125-6
Sulem P , Helgason H , Oddson A (2015) Identification of a large set of rare complete human knockouts. Nat Genet 47 448 - 452    DOI : 10.1038/ng.3243
Wang X , Grus WE , Zhang J (2006) Gene losses during human origins. PLoS Biol 4 e52 -    DOI : 10.1371/journal.pbio.0040052
Yngvadottir B , Xue Y , Searle S (2009) A genome-wide survey of the prevalence and evolutionary forces acting on human nonsense SNPs. Am J Hum Genet 84 224 - 234    DOI : 10.1016/j.ajhg.2009.01.008
Zhu J , Sanborn JZ , Diekhans M , Lowe CB , Pringle TH , Haussler D (2007) Comparative genomics search for losses of long-established genes on the human lineage. PLoS Comput Biol 3 e247 -    DOI : 10.1371/journal.pcbi.0030247
Bergfeld AK , Pearce OM , Diaz SL , Pham T , Varki A (2012) Metabolism of vertebrate amino sugars with N-glycolyl groups: elucidating the intracellular fate of the non-human sialic acid N-glycolylneuraminic acid. J Biol Chem 287 28865 - 28881    DOI : 10.1074/jbc.M112.363549
Chou HH , Takematsu H , Diaz S (1998) A mutation in human CMP-sialic acid hydroxylase occurred after the Homo-Pan divergence. Proc Natl Acad Sci U S A 95 11751 - 11756    DOI : 10.1073/pnas.95.20.11751
Varki NM , Strobert E , Dick EJ , Benirschke K , Varki A (2011) Biomedical differences between human and nonhuman hominids: potential roles for uniquely human aspects of sialic acid biology Annu Rev Pathol 6 365 - 393    DOI : 10.1146/annurev-pathol-011110-130315
Hayakawa T , Satta Y , Gagneux P , Varki A , Takahata N (2001) Alu-mediated inactivation of the human CMP-N-acetylneuraminic acid hydroxylase gene. Proc Natl Acad Sci U S A 98 11399 - 11404    DOI : 10.1073/pnas.191268198
Chou HH , Hayakawa T , Diaz S (2002) Inactivation of CMP-N-acetylneuraminic acid hydroxylase occurred prior to brain expansion during human evolution Proc Natl Acad Sci U S A 99 11736 - 11741    DOI : 10.1073/pnas.182257399
Hayakawa T , Aki I , Varki A , Satta Y , Takahata N (2006) Fixation of the human-specific CMP-N-acetylneuraminic acid hydroxylase pseudogene and implications of haplotype diversity for human evolution. Genetics 172 1139 - 1146    DOI : 10.1534/genetics.105.046995
Martin MJ , Rayner JC , Gagneux P , Barnwell JW , Varki A (2005) Evolution of human-chimpanzee differences in malaria susceptibility: relationship to human genetic loss of N-glycolylneuraminic acid. Proc Natl Acad Sci U S A 102 12819 - 12824    DOI : 10.1073/pnas.0503819102
Varki A , Gagneux P (2009) Human-specific evolution of sialic acid targets: explaining the malignant malaria mystery? Proc Natl Acad Sci U S A 106 14739 - 14740    DOI : 10.1073/pnas.0908196106
Liu W , Li Y , Learn GH (2010) Origin of the human malaria parasite Plasmodium falciparum in gorillas. Nature 467 420 - 425    DOI : 10.1038/nature09442
Takahashi T , Takano M , Kurebayashi Y (2014) N-glycolylneuraminic acid on human epithelial cells prevents entry of influenza A viruses that possess N-glycolylneuraminic acid binding ability. J Virol 88 8445 - 8456    DOI : 10.1128/JVI.00716-14
Dawkins R , Krebs JR (1979) Arms races between and within species. Proc R Soc Lond B Biol Sci 205 489 - 511    DOI : 10.1098/rspb.1979.0081
Desjardins PR , Burkman JM , Shrager JB , Allmond LA , Stedman HH (2002) Evolutionary implications of three novel members of the human sarcomeric myosin heavy chain gene family. Mol Biol Evol 19 375 - 393    DOI : 10.1093/oxfordjournals.molbev.a004093
Currie P (2004) Human genetics: muscling in on hominid evolution. Nature 428 373 - 374    DOI : 10.1038/428373a
Pennisi E (2004) Human evolution. The primate bite: brawn versus brain? Science 303 1957 -    DOI : 10.1126/science.303.5666.1957a
Perry GH , Verrelli BC , Stone AC (2005) Comparative analyses reveal a complex history of molecular evolution for human MYH16. Mol Biol Evol 22 379 - 382    DOI : 10.1093/molbev/msi004
McCollum MA , Sherwood CC , Vinyard CJ , Lovejoy CO , Schachat F (2006) Of muscle-bound crania and human brain evolution: the story behind the MYH16 headlines. J Hum Evol 50 232 - 236    DOI : 10.1016/j.jhevol.2005.10.003
Wroe S , Ferrara TL , McHenry CR , Curnoe D , Chamoli U (2010) The craniomandibular mechanics of being human. Proc Biol Sci 277 3579 - 3586    DOI : 10.1098/rspb.2010.0509
Hoh JF (2002) 'Superfast' or masticatory myosin and the evolution of jaw-closing muscles of vertebrates. J Exp Biol 205 2203 - 2210
Bachmanov AA , Beauchamp GK (2007) Taste receptor genes. Annu Rev Nutr 27 389 - 414    DOI : 10.1146/annurev.nutr.26.061505.111329
Li X , Li W , Wang H (2005) Pseudogenization of a sweet-receptor gene accounts for cats' indifference toward sugar. PLoS Genet 1 27 - 35    DOI : 10.1371/journal.pgen.0010027
Zhao H , Yang JR , Xu H , Zhang J (2010) Pseudogenization of the umami taste receptor gene Tas1r1 in the giant panda coincided with its dietary switch to bamboo. Mol Biol Evol 27 2669 - 2673    DOI : 10.1093/molbev/msq153
Jiang P , Josue J , Li X (2012) Major taste loss in carnivorous mammals. Proc Natl Acad Sci U S A 109 4956 - 4961    DOI : 10.1073/pnas.1118360109
Parry CM , Erkner A , le Coutre J (2004) Divergence of T2R chemosensory receptor families in humans, bonobos, and chimpanzees. Proc Natl Acad Sci U S A 101 14830 - 14834    DOI : 10.1073/pnas.0404894101
Hayakawa T , Suzuki-Hashido N , Matsui A , Go Y (2014) Frequent expansions of the bitter taste receptor gene repertoire during evolution of mammals in the Euarchontoglires clade. Mol Biol Evol 31 2018 - 2031    DOI : 10.1093/molbev/msu144
Perry GH , Kistler L , Kelaita MA , Sams AJ (2015) Insights into hominin phenotypic and dietary evolution from ancient DNA sequence data. J Hum Evol 79 55 - 63    DOI : 10.1016/j.jhevol.2014.10.018
Wang X , Thomas SD , Zhang J (2004) Relaxation of selective constraint and loss of function in the evolution of human bitter taste receptor genes. Hum Mol Genet 13 2671 - 2678    DOI : 10.1093/hmg/ddh289
Buck L , Axel R (1991) A novel multigene family may encode odorant receptors: a molecular basis for odor recognition. Cell 65 175 - 187    DOI : 10.1016/0092-8674(91)90418-X
Smith TD , Bhatnagar KP (2004) Microsmatic primates: reconsidering how and when size matters. Anat Rec B New Anat 279 24 - 31    DOI : 10.1002/ar.b.20026
Dong D , He G , Zhang S , Zhang Z (2009) Evolution of olfactory receptor genes in primates dominated by birth-and-death process. Genome Biol Evol 1 258 - 264    DOI : 10.1093/gbe/evp026
Barton RA (2006) Olfactory evolution and behavioral ecology in primates. Am J Primatol 68 545 - 558    DOI : 10.1002/ajp.20251
Niimura Y (2012) Olfactory receptor multigene family in vertebrates: from the viewpoint of evolutionary genomics. Curr Genomics 13 103 - 114    DOI : 10.2174/138920212799860706
Matsui A , Go Y , Niimura Y (2010) Degeneration of olfactory receptor gene repertories in primates: no direct link to full trichromatic vision. Mol Biol Evol 27 1192 - 1200    DOI : 10.1093/molbev/msq003
Bushdid C , Magnasco MO , Vosshall LB , Keller A (2014) Humans can discriminate more than 1 trillion olfactory stimuli. Science 343 1370 - 1372    DOI : 10.1126/science.1249168
Gerkin RC , Castro JB (2015) Humans can discriminate trillions of olfactory stimuli, or more, or fewer. arXiv 1502, 05120
Kiselyov K , van Rossum DB , Patterson RL (2010) TRPC channels in pheromone sensing. Vitam Horm 83 197 - 213
Vannier B , Peyton M , Boulay G (1999) Mouse trp2, the homologue of the human trpc2 pseudogene, encodes mTrp2, a store depletion-activated capacitative Ca2+entry channel. Proc Natl Acad Sci U S A 96 2060 - 2064    DOI : 10.1073/pnas.96.5.2060
Liman ER , Innan H (2003) Relaxed selective pressure on an essential component of pheromone transduction in primate evolution. Proc Natl Acad Sci U S A 100 3328 - 3332    DOI : 10.1073/pnas.0636123100
Lubke KT , Pause BM (2015) Always follow your nose: the functional significance of social chemosignals in human reproduction and survival. Horm Behav 68 134 - 144    DOI : 10.1016/j.yhbeh.2014.10.001
Su AI , Wiltshire T , Batalov S (2004) A gene atlas of the mouse and human protein-encoding transcriptomes. Proc Natl Acad Sci U S A 101 6062 - 6067    DOI : 10.1073/pnas.0400782101
Timmers HJ , Deinum J , Wevers RA , Lenders JW (2004) Congenital dopamine-β-hydroxylase deficiency in humans. Ann N Y Acad Sci 1018 520 - 523    DOI : 10.1196/annals.1296.064
Cubells JF , Sun X , Li W (2011) Linkage analysis of plasma dopamine β-hydroxylase activity in families of patients with schizophrenia. Hum Genet 130 635 - 643    DOI : 10.1007/s00439-011-0989-6
Combarros O , Warden DR , Hammond N (2010) The dopamine β-hydroxylase -1021C/T polymorphism is associated with the risk of Alzheimer's disease in the Epistasis Project. BMC Med Genet 11 162 -    DOI : 10.1186/1471-2350-11-162
Kim DS , Wang Y , Oh HJ , Lee K , Hahn Y (2014) Frequent loss and alteration of the MOXD2 gene in catarrhines and whales: a possible connection with the evolution of olfaction. PLoS One 9 e104085 -    DOI : 10.1371/journal.pone.0104085
Yu L , Jin W , Wang JX (2010) Characterization of TRPC2, an essential genetic component of VNS chemoreception, provides insights into the evolution of pheromonal olfaction in secondary-adapted marine mammals. Mol Biol Evol 27 1467 - 1477    DOI : 10.1093/molbev/msq027
Yim HS , Cho YS , Guang X (2014) Minke whale genome and aquatic adaptation in cetaceans. Nat Genet 46 88 - 92    DOI : 10.1038/ng.2835
McGowen MR , Clark C , Gatesy J (2008) The vestigial olfactory receptor subgenome of odontocete whales: phylogenetic congruence between gene-tree reconciliation and supermatrix methods. Syst Biol 57 574 - 590    DOI : 10.1080/10635150802304787
MacArthur DG , Tyler-Smith C (2010) Loss-of-function variants in the genomes of healthy humans. Hum Mol Genet 19 R125 - 130    DOI : 10.1093/hmg/ddq365
Kaiser J (2014) The hunt for missing genes. Science 344 687 - 689    DOI : 10.1126/science.344.6185.687
Alkuraya FS (2015) Human knockout research: new horizons and opportunities. Trends Genet 31 108 - 115    DOI : 10.1016/j.tig.2014.11.003
Stephens JC , Reich DE , Goldstein DB (1998) Dating the origin of the CCR5-D32 AIDS-resistance allele by the coalescence of haplotypes. Am J Hum Genet 62 1507 - 1515    DOI : 10.1086/301867
Xue Y , Daly A , Yngvadottir B (2006) Spread of an inactive form of caspase-12 in humans is due to recent positive selection. Am J Hum Genet 78 659 - 670    DOI : 10.1086/503116
Saleh M , Vaillancourt JP , Graham RK (2004) Differential modulation of endotoxin responsiveness by human caspase-12 polymorphisms. Nature 429 75 - 79    DOI : 10.1038/nature02451
North KN , Yang N , Wattanasirichaigoon D , Mills M , Easteal S , Beggs AH (1999) A common nonsense mutation results in a-actinin-3 deficiency in the general population. Nat Genet 21 353 - 354    DOI : 10.1038/7675
Go Y , Satta Y , Takenaka O , Takahata N (2005) Lineage-specific loss of function of bitter taste receptor genes in humans and nonhuman primates. Genetics 170 313 - 326    DOI : 10.1534/genetics.104.037523
Kim U , Wooding S , Ricci D , Jorde LB , Drayna D (2005) Worldwide haplotype diversity and coding sequence variation at human bitter taste receptor loci. Hum Mutat 26 199 - 204    DOI : 10.1002/humu.20203
Pronin AN , Xu H , Tang H , Zhang L , Li Q , Li X (2007) Specific alleles of bitter receptor genes influence human sensitivity to the bitterness of aloin and saccharin. Curr Biol 17 1403 - 1408    DOI : 10.1016/j.cub.2007.07.046
Roudnitzky N , Bufe B , Thalmann S (2011) Genomic, genetic and functional dissection of bitter taste responses to artificial sweeteners. Hum Mol Genet 20 3437 - 3449    DOI : 10.1093/hmg/ddr252
Samson M , Labbe O , Mollereau C , Vassart G , Parmentier M (1996) Molecular cloning and functional expression of a new human CC-chemokine receptor gene. Biochemistry 35 3362 - 3367    DOI : 10.1021/bi952950g
Dragic T , Litwin V , Allaway GP (1996) HIV-1 entry into CD4+cells is mediated by the chemokine receptor CC-CKR-5. Nature 381 667 - 673    DOI : 10.1038/381667a0
Deng H , Liu R , Ellmeier W (1996) Identification of a major co-receptor for primary isolates of HIV-1. Nature 381 661 - 666    DOI : 10.1038/381661a0
Liu R , Paxton WA , Choe S (1996) Homozygous defect in HIV-1 coreceptor accounts for resistance of some multiply-exposed individuals to HIV-1 infection. Cell 86 367 - 377    DOI : 10.1016/S0092-8674(00)80110-5
Sabeti PC , Walsh E , Schaffner SF (2005) The case for selection at CCR5-D32. PLoS Biol 3 e378 -    DOI : 10.1371/journal.pbio.0030378
Hutter G , Nowak D , Mossner M (2009) Long-term control of HIV by CCR5 Delta32/Delta32 stem-cell transplantation. N Engl J Med 360 692 - 698    DOI : 10.1056/NEJMoa0802905
Tebas P , Stein D , Tang WW (2014) Gene editing of CCR5 in autologous CD4 T cells of persons infected with HIV. N Engl J Med 370 901 - 910    DOI : 10.1056/NEJMoa1300662
Alnemri ES , Livingston DJ , Nicholson DW (1996) Human ICE/CED-3 protease nomenclature. Cell 87 171 -    DOI : 10.1016/S0092-8674(00)81334-3
Fischer H , Koenig U , Eckhart L , Tschachler E (2002) Human caspase 12 has acquired deleterious mutations. Biochem Biophys Res Commun 293 722 - 726    DOI : 10.1016/S0006-291X(02)00289-9
Beggs AH , Byers TJ , Knoll JH , Boyce FM , Bruns GA , Kunkel LM (1992) Cloning and characterization of two human skeletal muscle alpha-actinin genes located on chromosomes 1 and 11. J Biol Chem 267 9281 - 9288
Mills M , Yang N , Weinberger R (2001) Differential expression of the actin-binding proteins, α-actinin-2 and -3, in different species: implications for the evolution of functional redundancy. Hum Mol Genet 10 1335 - 1346    DOI : 10.1093/hmg/10.13.1335
Yang N , MacArthur DG , Gulbin JP (2003) ACTN3 genotype is associated with human elite athletic performance. Am J Hum Genet 73 627 - 631    DOI : 10.1086/377590
Niemi AK , Majamaa K (2005) Mitochondrial DNA and ACTN3 genotypes in Finnish elite endurance and sprint athletes. Eur J Hum Genet 13 965 - 969    DOI : 10.1038/sj.ejhg.5201438
Roth SM , Walsh S , Liu D , Metter EJ , Ferrucci L , Hurley BF (2008) The ACTN3 R577X nonsense allele is under-represented in elite-level strength athletes. Eur J Hum Genet 16 391 - 394    DOI : 10.1038/sj.ejhg.5201964
Bramble DM , Lieberman DE (2004) Endurance running and the evolution of Homo. Nature 432 345 - 352    DOI : 10.1038/nature03052
MacArthur DG , Seto JT , Raftery JM (2007) Loss of ACTN3 gene function alters mouse muscle metabolism and shows evidence of positive selection in humans. Nat Genet 39 1261 - 1265    DOI : 10.1038/ng2122
Ruxton GD , Wilkinson DM (2013) Endurance running and its relevance to scavenging by early hominins. Evolution 67 861 - 867    DOI : 10.1111/j.1558-5646.2012.01815.x
Lin YL , Pavlidis P , Karakoc E , Ajay J , Gokcumen O (2015) The evolution and functional impact of human deletion variants shared with archaic hominin genomes. Mol Biol Evol 32 1008 - 1019    DOI : 10.1093/molbev/msu405