Table 1.

Representative list of human-specific genetic changes linked to phenotypes

Genetic feature	Type of change	Evolutionary relevance	Proposed mechanism	Phenotypic impact	Refs.
AMY1	Copy number change	Polymorphic in human populations	Higher copy number of AMY1 leads to enhanced starch degradation through amylase enzyme activity in salivary glands	Increased starch digestion capacity correlated with gene copy number and salivary amylase levels	25
AQP7	Copy number change	Human specific	Increased water and glycerol transport	Might augment endurance running in humans	75
ARHGAP11B	Segmental duplication	Human specific	Loss of Rho GAP activity owing to a change in splice site	Basal progenitor amplification and neocortex expansion in mouse and marmoset models	165,166,168
BOLA2	Segmental duplication	Human specific	Correlation of gene copy number with RNA expression and protein levels	Iron homeostasis and susceptibility to anaemia	297,298
CCL3L1	Segmental duplication	Polymorphic in humans	HIV-1-suppressing chemokine	Lower copy numbers associated with AIDS susceptibility	299
CMAH	Pseudogene	Human specific	92-bp deletion in sialic acid hydroxylase domain leads to inactivation of enzyme activity that converts CMP-Neu5Ac into CMP-Neu5Gc	Atherosclerosis predisposition; xenosialitis through circulating anti-Neu5Gc; immunological changes; changes in muscle fatigue	182,183,300–302
FOXP2	Two single nucleotide substitutions positively selected (debated)	Human specific	Regulation of cortico-striatal circuit development	Involved in speech and language capability	163,178,303
GHRD3	Deletion of an exon	Human specific	Growth hormone receptor gene is affected	Associated with the response to nutritional defects along the evolutionary time course	304
HACNS1 (HAR2)	Single nucleotide substitutions	Human specific	Regulates GBX2 expression (positively selected)	Associated with digit, limb and pharyngeal arch patterning	155,159
HAR1	Single nucleotide substitutions	Human specific	Modification of the primary sequence and secondary structure of a non-coding RNA gene	Expressed in Cajal–Retzius cells and other brain regions during development	70
HYDIN2	Segmental duplication	Human specific	Promoter modification altered tissue specificity of HYDIN2 isoforms in cerebellum and cerebral cortex	Potentially involved in neurodevelopmental disorders	305
NBPF	Oludvai/DUF1220 protein domain copy number change	Human specific	DUF1220 domain dosage-associated increase in neural stem cell proliferation	Brain size and 1q21.1 syndrome	62,306,307
NOTCH2NL	Segmental duplication	Human specific	Expressed in radial glia stem cells and tunes neuronal differentiation via NOTCH signalling	Associated with expanded neocortex, observed at breakpoints in 1q21.1 deletion/duplication syndrome	170,171
NOVA1	Single nucleotide substitution	Modern human specific	Affecting alternative splicing during nervous system development	Altering excitatory synaptic interactions and involvement in neurological disorders	264,308
Regulatory element of AR (hCONDEL569)	Deletion of a highly conserved regulatory element	Human specific	Mouse and chimpanzee enhancer sequences drive lacZ expression in mouse model at facial vibrissae and genital tubercle	Potential regulation of AR expression by the loss of this regulatory element leading to loss of sensory vibrissae and penile spines	72
Regulatory element of CACNA1C	Large tandem repeats	Human specific	Intronic tandem repeat array of neurodevelopmental enhancer resulting in stronger gene expression in humans	Increased expression of human CACNA1C during human neurodevelopment potentially linked to bipolar disorder and schizophrenia	44
Regulatory element of CUX1 (HAR426)	Single nucleotide polymorphism	Human specific	G>A mutation within HAR426. CUX1 promoter and HAR426 interaction is likely to affect gene expression levels	Rare disease might affect dendritic spine density and synaptogenesis	43,309
Regulatory element of FZD8 (HARE5)	Human accelerated enhancer	Human specific	Developmental enhancer physically interacting with FZD8 promoter	Accelerated neural progenitor cell cycle and increased neocortex size in a mouse model	156
Regulatory element of GADD45G (hCONDEL332)	Deletion of a highly conserved regulatory element	Human specific	Mouse and chimpanzee enhancer sequences drive lacZ expression in the mouse ventral forebrain	Potential expansion of particular inhibitory neuron populations	72
Regulatory element of GDF5–UQCC locus	Single nucleotide polymorphism	Polymorphic in human populations	Chromatin accessibility profiles of joint chondrocytes reveal positively selected regulatory variants	Affecting knee shape in humans and associated with osteoarthritis risk	37
Regulatory element of LCT	Single nucleotide polymorphism	Polymorphic in human populations	Selective sweeps in the enhancer region enhance lactase expression in certain humans	Milk product digestion into adulthood (lactase persistence) and potentially other phenotypes	24
Regulatory element of PPP1R17 (HAR2635 and HAR2636)	HAR	Human specific	Chromatin contact of PPP1R17 promoter and HAR2635 and HAR2636	Acting as neurodevelopmental enhancer that may extend cell-cycle length in humans	148
SIGLEC13	Gene loss	Human specific	Alu-mediated recombination	Resistance to sialylated bacterial infections	310,311
SLC22A4	Single nucleotide polymorphism	Polymorphic in human populations	Ergothioneine transporter	Crohn’s disease, rheumatoid arthritis	312–314
SLC24A5	Single nucleotide polymorphism	Polymorphic in human populations	UV radiation-induced transporter activity	Variable skin pigmentation	315,316
SLC6A11	Single nucleotide polymorphism	Polymorphic in human populations	Single nucleotide change in a coding region	Expressed in liver and modulating triacylglycerol metabolism, potential type 2 diabetes risk factor	317
SRGAP2	Segmental duplication	Human specific	Rho GAP family member SRGAP2 paralogues expressed in the developing human cortex. SRGAP2B and SRGAP2C are truncated duplications that antagonize by dimerizing with the ancestral form of SRGAP2	Affect dendritic spine density and morphology	173,174,318
TBC1D3	Segmental duplication	Great ape specific	Affecting neural progenitor proliferation by inhibiting histone methyltransferase G9A	Cortical expansion and folding	319,320
TBXT	Intronic Alu insertion	Ape specific	Alternative splicing of TBXT	Associated with tail reduction or loss in mouse model of splicing change	321

HAR, human accelerated region; hCONDEL, human conserved deletion.