Table 3.
Some candidate genes and gene families that may contribute to phenotypic differences between humans and apesa
|
Gene(s) |
Gene product(s) |
Unusual hominid or human-specific features |
Potential relevance to the human condition |
|---|---|---|---|
| Individual genes | |||
| FOXP2 | Putative transcription factor with polyglutamine tract and forkhead DNA binding domain | Two human-specific amino acid changes | Mutant humans have motoric speech disorder (developmental verbal dyspraxia). Region positively selected and fixed in humans <200,000 years ago (Enard et al. 2002b; Zhang et al. 2002) |
| MYH16 | Myosin heavy chain 16 | Human-specific 2-bp deletion causing frameshift—predicted 76-kD unstable head domain | Claimed to be cause of reduction in the type II fibres of human jaw muscle. (Stedman et al. 2004; Perry et al. 2005) |
| CMAH | CMP-Neu5Ac hydroxylase | 92-bp deletion of exon 6 causing frameshift and inactive enzyme. Fixed in modern humans | Absence of sialic acid Neu5Gc. Change in resistance or susceptibility to pathogens. Loss of ligand for some Siglecs. Dated ∼2.5–3 Mya. Dietary Neu5Gc in meat became foreign antigen (Chou et al. 1998, 2002; Irie et al. 1998; Hayakawa et al. 2001) |
| MAOA | Monoamine oxidase A | Human-specific nonconservative change Glu151Lys in active site | Substitution affects protein dimerization according to a 3D structural model and predicts functional change (Andres et al. 2004) |
| ASPM | Modulator of mitotic spindle in neural progenitors? | Accelerated evolution in ape and human lineages | Deletions in ASPM lead to microcephaly. Presumed to be related to increased brain size and/or other features of human brain (Zhang 2003; Dorus et al. 2004; Evans et al. 2004; Kouprina et al. 2004b; Mekel-Bobrov et al. 2005) |
| MCPH1 | Microcephalin | As above | As above (Dorus et al. 2004; Evans et al. 2004, 2005) |
| TTR | Transthyretin | Decreased expression in humans in blood and brain | May be related to altered thyroid hormone metabolism in humans versus chimpanzees (Gagneux et al. 2001) |
| ST6GAL1 | Alpha 2–6 sialyltransferase | Apparent human-specific up-regulation on epithelia | Can explain relative resistance of chimpanzees to human influenza A virus. Other consequences unknown. (Gagneux et al. 2003) |
| EMR4 | EGF-TM7 receptor family | Human-specific deletion in exon 8. Frameshift | Predominantly expressed by immune system cells. Functional significance unknown (Hamann et al. 2003) |
| PCDH11Y | Protocadherin XY | Duplicated onto Y in Yp11.2/Xq21.3 pseudoautosomal region only in humans | Expressed from Y and escapes X-inactivation? Y copy has undergone structural changes. Selectively expressed in brain. Probable adhesion molecule. Significance unknown, hypothesized to be involved in brain development, lateralization and schizophrenia risk (Ross et al. 2003; Blanco-Arias et al. 2004) |
| IL9R (Y) | Interleukin-9 receptor | As above | Expressed from Y and escapes X-inactivation? Growth factor for T cells, mast cells, and macrophages. Significance unknown. Related to asthma? (Vermeesch et al. 1997) |
| SPRY3 | Sprouty 3 | As above | Expressed from Y and escapes X-inactivation? Cysteine-rich protein—Homolog of Drosophila antagonist of FGF signaling that patterns apical airways branching. Significance unknown (Vermeesch et al. 1997) |
| SYBL1 | Synaptobrevin-like | As above | Inactive on Y chromosome? Significance unknown (Vermeesch et al. 1997) |
| KRTHAP1 | Type 1 acidic hair keratin | Human-specific single bp substitution and termination codon | Different hair keratin expression pattern noted in the hair follicle. Inactivated 0.25 Mya? Possibly related to human:ape differences in hair (Winter et al. 2001) |
| RLN | Relaxin hormone | Human-specific expression in placenta and corpus luteum | Possibly related to differences in reproductive biology (Evans et al. 1994) |
| ELN | Tropoelastin | 2 exons deleted. Open reading frame maintained | Extracellular matrix component, including vascular wall. Alteration in vascular wall structure? (Szabo et al. 1999) |
| SIGLEC11 | Siglec-11 | Human-specific gene conversion by adjacent pseudogene, maintaining ORF | Change in binding specificity for sialic acids. Human-specific expression in brain microglia. Biological consequences unknown (Hayakawa et al. 2005) |
| CASP12P1 | Caspase-12—cysteine protease related to ICE subfamily | Human-specific disruption of SHG box required for activity. Premature stop codon also in most humans | In rodents, Casp12 mediates apoptosis in response to ER stress. Human SNP can restore full-length caspase proenzyme which confers hypo-responsiveness to LPS-stimulated cytokine production but has no significant effect on apoptotic sensitivity. (Fischer et al. 2002) |
| Gene families | |||
| OR (17p13, etc.) | Olfactory receptors | Many more human pseudogenes and fewer active genes in this large family | Related to diminished human olfactory capabilities? However, some intact genes show evidence of positive selection (Gilad et al. 2003a,b 2004) |
| TAS2R (12p13, 7q31, 7q34, etc.) | Bitter taste receptors | Fixation of loss-of-function mutations | Proposed relaxation of selective constraint and loss of function (Wang et al. 2004; Fischer et al. 2005) |
| SIGLEC (19q13) | CD33-related innate immune system regulating genes | Mutations, deletions, gene conversions, expression changes | Sialic acid recognizing signaling receptors. Changes in binding, expression patterns, etc. Could be partly a secondary consequence of human loss of Neu5Gc (Angata et al. 2001; Sonnenburg et al. 2004; The Chimpanzee Sequencing and Analysis Consortium 2005) |
| COX (multiple locations) | Mitochondria cytochrome oxidase subunits | Multiple genes show rapid evolution in hominids. COX5A specifically in humans | Altered electron transport chain. Enhanced oxidative phosphorylation postulated to support increased brain energy consumption? (Grossman et al. 2004; Goodman et al. 2005) |
| SPANX (Xq27.1) | Sperm proteins associated with nucleus—genes on X chromosome | SPANX-C is specific to humans. SPANX-B has duplicated in humans | Rapidly evolving in all hominids. Expressed in normal testis, and in some cancers (Kouprina et al. 2004a) |
| Morpheus (multiple locations) | Proteins not characterized yet | Contained within large duplicated regions in humans and apes | Evidence of rapid evolution. Most extreme case of positive selection among hominids. Some human-specific sequences. Functional significance uncertain (Johnson et al. 2001) |
| LILR (19q13.4) | Leukocyte Ig-like receptors | Rapid evolution, only few clear orthologs between chimpanzee and human | Part of a larger family of genes. Involved in recognizing “self” via molecules like MHC (Canavez et al. 2001) |
| KIR (19q13.4) | Killer inhibitory receptors | Rapid evolution, only few orthologs clear between chimpanzee and human | Expressed in NK cells. Recognize “self” molecules like MHC (Hao and Nei 2005; Sambrook et al. 2005) |
| TRG (7p14) | T cell receptors | 4 TCRs are pseudogenes in humans | Part of a larger family of genes. Functional significance uncertain (Meyer-Oslon et al. 2003) |
| FCGR1 (1p and 1q) | High affinity IgG-Fc receptors | Pericentric inversion, distinguishing human from chimpanzee chromosome 1 | Functional significance of inversion uncertain (Maresco et al. 1998) |
| IGKV (2p11.2) | κ light chains of immunoglobulins | Possible human specific duplication | Part of a larger family of genes. Functional significance uncertain (Ermert et al. 1995) |
| GYP (4q28-q31, 2q14-q21) | Glycophorins | Accelerated evolution in humans | Red blood cell proteins. Rapid evolution of extra cellular domain, likely due to selection pressure by merozoite stage of Plasmodium falciparum (Rearden et al. 1990; Baum et al. 2002; Wang et al. 2003) |
| LCE (1q21) | Epidermal differentiation complex | High density of rapidly evolving genes | Proteins that help form the cornified layer of the skin barrier (Marshall et al. 2001; The Chimpanzee Sequencing and Analysis Consortium 2005) |
| CST (20p11) | Cystatins | As above | Physiological cysteine proteinase inhibitors (The Chimpanzee Sequencing and Analysis Consortium 2005) |
| PSG (19q13) | Pregnancy-specific β-1-glycoproteins | As above | High quantities secreted by placental trophoblasts. Exact physiologic role during pregnancy unknown (The Chimpanzee Sequencing and Analysis Consortium 2005) |
| KRT (17q21) | Hair keratins and keratin-associated proteins | As above | Major components of the cytoskeleton in hair and skin epithelial cells (The Chimpanzee Sequencing and Analysis Consortium 2005) |
| WFDC (20q13)
|
Protein domains with homology to whey acidic protein (WAP)
|
As above
|
Postulated protease inhibitors. Possible host defense against invading micro-organisms or regulation of endogenous proteolytic
enzymes (The Chimpanzee Sequencing and Analysis Consortium 2005)
|
-
↵a This list is not meant to be exhaustive. It also does not include genes that have specifically changed in chimpanzees, but not in humans (e.g., MICA/B, HLA); genes that are polymorphic within humans (e.g., APOE, COMT); or instances in which a human disease-causing amino acid mutation appears to be the wild-type state in the chimpanzee (e.g., AIRE, MKKS, MLH1, MYOC, OTC, and PRSS1)
