Human EvolutionGenes and Genomes

Lecture 2: Becoming Human

Professor Mark Pallen

Humans are not chimpsBipedalism, with resulting

changes in post-cranial anatomy (S-shaped spine, bowl-like pelvis)

Brain size increased, head shape changed (strong chin, small snout, larger brain case)

Smaller canines, less robust musculature

Loss of thick body hairDifferences in disease

susceptibility

What can genes and genomes hope to tell us?

Exact genome-wide divergence (& its variation across the genome)Estimation of time of divergence from the

closest relativesThe mode of genome evolutionThe mode of speciation

Human-specific changes in the genomeWhat differences in our genome make us

human?Genes involved in evolution of brain and speechDiscovery of genetic variants that might

contribute to disease susceptibility in humans

Human genome: complete

Chimp genome: draft

Orang genome: in progress

Macaque genome: draft

Neanderthal genome sample sequenced

Genomes sequenced

Single male chimp: Clint

What makes us human?

Candidate gene approach• examine genes likely to be involved in

specific traits of interestComparative genomics approach

• Look for differences in genome, especially regions that have undergone positive selection

• BUT 35 million bp of difference and needle in a haystack problem

What makes us human?

No easy answer! Most evolutionary change is due to neutral

driftAdaptive changes constitute only a small

fraction of the changes between speciesNo simple linear relationship between

morphological changes and sequence variation• gross morphological differences

human/chimp >> differences between two mouse species with same %DNA difference

• marked variation among dogs, but all show little sequence variation (0.15%)

Human & Chimp Genomes

The number of chromosomes differsChanges in chromosome structureMultiple insertions and deletions: about

90Mb of DNA is either human or chimp-specific

Gene duplicationGene lossEvolution of gene expression

HumanChromosome 2

ChimpanzeeChromosomes 2a & 2b

Chromosome fusion:

Segmental duplications:

Humans: 13.7%Chimps: ~5%

of the genome is segmentally duplicated

Inversions:

Multiple inversions between humans and chimpanzees

Translocations: In humans

an X=>Y translocation resulted in formation of

the second pseudo- autosomal region

Changes in chromosome structure

Modes and models of evolution

Search for human-specific changes in

gene expression

Human bonobo chimp gorilla

A set of genes with human-

specific changes in expression

Evolution of gene expression

Pollard et al Nature 2006

Human & Chimp Genomes

Single nucleotide substitutions occur at rate of 1.23%

Orthologous proteins on average differ by only two amino acids, one in each lineage• 29% of proteins identical

Differences in endogenous retroviruses• HERV-K in humans; PtERV1 and 2 in chimp

More Alu repeat activity in humans

Differences in biologyApoptosis

• caspase-12 disrupted in humans; intact in mice and chimps

• ?related to susceptibility to Alzheimer’s?Inflammation

• IL1F7, IL1F8, ICEBERG all missing in chimpsParasite resistance

• APOL1/APOL4 missing in chimps; altered resistance to Trypanosomes?

Sialic acid biology• CMAH gene• underlies differences in susceptibility to

malaria and AIDS?

FOXP2Identified as site of Mendelian dominant mutation in

human KE family, afflicted with speech difficultiesmissense mutation (R553H) in the forkhead domain of FOXP2

cosegregates with the disorder in this familyRegulatory protein; contains forkhead domain; shown to

regulate hundreds of genes in brain, including CNTNAP2(Spiteri et al 2007).

Often dubbed “the language gene” but also involved in motor co-ordinationNeuroimaging studies show anomalies in basal ganglia

morphology and activity. Embryological studies then showed that in mouse and

human FOXP2 modulates development of the basal gangliaConvergent evolution in bird song (and bat echolocation?)

Mutations in the human FOXP2 gene are associated with an autosomal dominant form of dysarthria (difficulty in articulating speech). The human

FOXP2 gene shows changes in amino acid coding and a pattern of nucleotide polymorphisms that suggest this gene has undergone positive

selection during recent human evolution

(Enard et al 2002 Nature)

Evolution of human FOXP2 gene

FOXP2 in miceFoxP2 knock-outs in mice:

developmental delays; defects in ultrasonic communication; effects on basal ganglia

Severe in homozygotes; less so in heterozygotesFoxP2 R553H knock-in mice:

Homozygous: severe developmental problems; defects in ultrasonic communication; similar but less severe in heterozygotes

Humanised FoxP2 knock-in mice:generally healthy, different ultrasonic vocalizations, decreased

exploratory behavior, decreased dopamine concentrations in brain

increased dendrite lengths and increased synaptic plasticity in striatum/basal ganglia.

Note of caution in interpreting these changes

HAR1 Human accelerated region 1

2/118 differences chicken-chimp18/118 differences chimp-human

Non-protein-coding RNA gene Expressed during cortical development

Two distinct experimentally supported secondary structure models for HAR1 RNAs

Beniaminov A et al. RNA 2008;14:1270-1275

AMY1Encodes amylaseMultiple copies in mammalian genomes

But many more copies in humansPeople with most copies produce most amylase in

salivaPeople with high-starch diets have, on average,

more AMY1 copies than those with traditionally low-starch diets

Provides immediate access to glucose from starch?role in recovering more calories from diet more

quickly? Protection against effects of GI upset

“Brain-building” genesASPM and Microcephalin identified in

microcephaly patientsAlong with MCPH1, CDK5RAP2 and CENJASPM crucial for control of cell division in

neuroepithelial cellsBoth experienced bursts of change during

primate evolution, including in human lineage since divergence from chimps

Two controversial Science papers from Sep 9, 2005

variants more common in Eurasians than in Africans…

Subsequent studies find no links found between microcephalin variant and IQ or brain sizeAND these genes are also expressed outside the brain

Merely tracking out of Africa migration?

MYH16

MYH16

KRTHAP1

HAR2/HACNS1

“The dexterity of the human hand is due to morphological differences compared with other primates that include rotation of the thumb toward the palm and an increase in the length of the thumb relative to the other digits. Human-specific changes in hindlimb morphology, such as the characteristic inflexibility and shortened digits of the human foot, facilitated habitual bipedalism. The gain of function in HACNS1 may have influenced the evolution of these or other human limb features by altering the expression of nearby genes during limb development.”

SummaryChimpanzee genome

Differences of many sorts from SNPs to chromosome structure

Some key differences in biologyChimp allele is a disease allele in humans in several

genesCandidate Genes: FoxP2, Amy1, Har1/2,

Microcephalin, ASPM Macaque Genome

Triangulation allows determination of polarity of human-chimp changes

Macaque allele is a disease allele in humans in several genes

Genes undergoing positive selection identified