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Review
. 2009;10:355-86.
doi: 10.1146/annurev.genom.9.081307.164420.

Sequencing Primate Genomes: What Have We Learned?

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Free PMC article
Review

Sequencing Primate Genomes: What Have We Learned?

Tomas Marques-Bonet et al. Annu Rev Genomics Hum Genet. .
Free PMC article

Abstract

We summarize the progress in whole-genome sequencing and analyses of primate genomes. These emerging genome datasets have broadened our understanding of primate genome evolution revealing unexpected and complex patterns of evolutionary change. This includes the characterization of genome structural variation, episodic changes in the repeat landscape, differences in gene expression, new models regarding speciation, and the ephemeral nature of the recombination landscape. The functional characterization of genomic differences important in primate speciation and adaptation remains a significant challenge. Limited access to biological materials, the lack of detailed phenotypic data and the endangered status of many critical primate species have significantly attenuated research into the genetic basis of primate evolution. Next-generation sequencing technologies promise to greatly expand the number of available primate genome sequences; however, such draft genome sequences will likely miss critical genetic differences within complex genomic regions unless dedicated efforts are put forward to understand the full spectrum of genetic variation.

Figures

Figure 1
Figure 1
Primate genome sequencing status. Primate whole-genome sequencing projects (10/25/08) with respect to the generally accepted primate phylogeny and an outgroup (mouse). Divergence times are estimated based on millions of years according to Goodman et al. 1998.
Figure 2
Figure 2
Human and primate sequence similarity. Whole-genome shotgun sequences from a human (blue), chimpanzee (red), and macaque (brown) were aligned against the human reference genome and the nucleotide divergence was computed in 100-kbp windows along (a) chromosome 2 and (b) chromosome 7. Note the increase in sequence divergence within 10 Mb of the telomere.
Figure 3
Figure 3
A human-accelerated region of single-basepair substitution, HAR1F. (a) A highly conserved noncoding DNA segment, HAR1F, shows an excess of substitutions within the human lineage based on a multiple sequence alignment (123). (b) HAR1F is transcribed into a noncoding RNA. Many of the single-basepair substitutions correspond to compensatory changes within the context of RNA secondary structure ( yellow–blue denotes compensatory mutations, purple denotes substitutions in unpaired regions, and red denotes noncompensatory changes).
Figure 4
Figure 4
HACNS1 human-accelerated mutations create a limb enhancer. (a) Multiple sequence alignment of the putative enhancer HACNS1 with other vertebrate genomes shows an excess of 13 human-specific substitutions (red ). (b) Transgenic mouse lacZ expression pattern using an enhancer in which the 13 human-specific substitutions were introduced against the orthologous chimpanzee sequence background. (c) Expression pattern using an enhancer reverting the substitutions in the human sequence to the nucleotide states in chimpanzee and rhesus. These results show that those substitutions drive strong gene expression within the limbs.
Figure 5
Figure 5
Core duplication hypothesis of human segmental duplications. Duplicative transposition or biased gene conversion duplicates copies to new locations with different unique sequences flanking the duplicated copy of the core; a secondary duplication moves into a third location but also carries flanking duplicons from the second locus to the third; the process repeats itself during the course of evolution, leading to the formation of large complex blocks of intrachromosomal segmental duplication along the chromosome that can now promote nonallelic homologous recombination. These events occur before and after speciation, leading to both lineage-specific and shared duplication blocks between closely related species. Segmental duplications located at the periphery are more likely to be evolutionary young or lineage specific (e.g., duplication D), whereas the core is common to all the duplication blocks. Paralogous sequence exchanges can occur between loci changing the sequence and erasing evolutionary history. Data based on primate comparative sequencing (78) and evolutionary reconstruction of human segmental duplications (77).
Figure 6
Figure 6
A burst of PTERV1 retroviral insertions in African great apes and Old World monkey species but not orangutan or human. (a) Whole-genome landscape of PTERV1 integration sites is shown using the human chromosomes as a reference (build35). (b) A detailed view on one chromosome (chromosome 2) is shown. While some species has been massively plagued by the retrovirus that integrated into the germline (chimpanzee, gorilla, macaque, and baboon), other species (human and orangutan) are unusually devoid. Furthermore, 95% of these sites were found to be in nonorthologous locations when compared between species, suggesting episodic events early in the history of each of these species potentially from an exogenous source.
Figure 7
Figure 7
Demographic parameters and speciation times of humans and great apes. Current population sizes (red; IUCSN list of threatened species at http://www.iucnredlist.org/), effective population sizes, and estimated ancestral population sizes (blue) are shown in thousands of individuals for each hominid species and subspecies. Divergence times in either millions of years (Mya) or thousands of years (Kya) are indicated. Population genetic parameters are based on diversity data presented in the following papers: Wall (158), Won & Hey (163), Becquet & Przeworski (13), Hobolth et al. (66), Burgess & Yang (19), Steiper (141), and Caswell et al. (26). ∗ correspond to most of the studies but Burgess & Yang (19) suggested a lower bond of 14 Mya to 22 Mya.
Figure 8
Figure 8
Recombination hotspots vary between chimpanzee and human. (a) Distribution of shared hotspots under two statistical models. In the first model (blue) all the hotspots are independent and in the second (red ) all hotspots are shared. The observed proportion of shared hotspots (8%) suggests that allelic hotspots of recombination evolve rapidly and change over short periods of evolutionary time. (b) On a broader scale, the recombination rates (measured in 50-Kb windows) correlate, suggesting that the landscape of recombination remains relatively constant.
Figure 9
Figure 9
Limitations of whole-genome shotgun sequencing of primate genomes. A comparison of two genome assembly methods for human chromosome 16 is shown (138). Top line represents the chromosome 16 assembly based on hierarchical sequencing of large insert clones (IHGSC, 2005) (94) while bottom line represents the genome based strictly on whole-genome shotgun sequence assembly of sequence reads from capillary sequencers (70). The WGSA assembly is ~ 20 Mbp shorter than the clone-based assembly and is missing primarily duplicated sequences (middle line). The missing material is highly duplicated (28 distinct regions), carries a rapidly evolving human-great ape gene family (78), and is a breakpoint for microdeletions associated with mental retardation and autism. The WGSA assembly is missing most of this material and fails to map most of the loci. This effect is expected to be exacerbated with next-generation sequence technology where the average read length is currently significantly shorter than capillary sequencing methods.

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