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Evolution of genetic and genomic features unique to the human lineage

Key Points

  • Here we provide an overview of the major findings related to human-lineage-specific (HLS) genomic and genetic changes and describe how these findings might relate to human-specific traits.

  • The range of HLS changes extends from large-scale (for example, cytogenetic) to small-scale (for example, single-nucleotide substitutions), and current advances in genomic technologies are allowing genomic comparisons to be made with unprecedented scope and detail.

  • A representative sampling of several types of genetic changes that can occur, as well as several important gene families that have undergone multiple HLS events, is presented alongside the possible phenotypic implications of these changes.

  • Associating HLS genetic changes with a trait is one of the most challenging tasks for human evolutionary genomic research. A discussion of strategies to connect the two is presented, along with a list of current data available.

  • There is emerging evidence that many HLS genetic and genomic changes colocalize with disease-associated genomic regions, suggesting a mechanistic link between the two.

Abstract

Given the unprecedented tools that are now available for rapidly comparing genomes, the identification and study of genetic and genomic changes that are unique to our species have accelerated, and we are entering a golden age of human evolutionary genomics. Here we provide an overview of these efforts, highlighting important recent discoveries, examples of the different types of human-specific genomic and genetic changes identified, and salient trends, such as the localization of evolutionary adaptive changes to complex loci that are highly enriched for disease associations. Finally, we discuss the remaining challenges, such as the incomplete nature of current genome sequence assemblies and difficulties in linking human-specific genomic changes to human-specific phenotypic traits.

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Figure 1: Genome positions of human-lineage-specific gene changes.

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Acknowledgements

We would like to thank S. O'Bleness for editorial comments, M. Dickens for graphics assistance and J. Noonan for access to published images. We also thank the many student and faculty contributors to the Matrix of Comparative Anthropogeny (MOCA) website. Work in our laboratories has been supported by the US National Institutes of Health and by the Mathers Foundation of New York, which also supports the MOCA website.

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Correspondence to James M. Sikela.

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James M. Sikela is the founder of and a shareholder in GATC Science, LLC. Ajit Varki is a co-founder of and shareholder in Sialix, Inc. Majesta O'Bleness, Veronica Searles and Pascal Gagneux declare no competing financial interests.

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Ajit Varki's homepage

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Center for Academic Training and Research in Anthropogeny (CARTA)

Matrix of Comparative Anthropogeny (MOCA)

OMIM — Online Mendelian Inheritance in Man

Glossary

Accelerated evolution

More nucleotide or copy number changes in a particular region or gene than would be expected from background rates of mutation over time (for example, in cytochrome c oxidase subunit Va (COX5A)).

Copy number changes

Increases or decreases in the number of copies of a gene or segment (for example, in SLIT–ROBO rho GTPase-activating protein 2 (SRGAP2)).

Fluorescent in situ hybridization

(FISH). A technique used to visualize the location of specific DNA sequences on chromosomes.

Array-based comparative genomic hybridization

(Array CGH). A microarray- based method for detecting copy number variation in the genome.

Protein domains

Discrete portions of a protein sequence that may evolve and function independently of the rest of the protein (for example, in the DUF1220 domain).

Domain amplification

Intragenic copy number increase of a protein domain (for example, in the DUF1220 domain).

Amino acid change

A DNA change that leads to a change at the protein sequence level (for example, in forkhead box P2 (FOXP2)).

Pseudogenization

Loss of gene function while most of the gene is retained (for example, in apolipoprotein C1 (APOC1)).

'Less-is-more' hypothesis

The hypothesis that gene loss has a major role in evolution.

Polymorphisms

Allelic genetic variations within a species (for example, in amylase, alpha 1A (AMY1A)).

Gene conversion

'Pasting' of identity from one homologous gene to another (for example, in sialic-acid-binding Ig superfamily lectin 11 (SIGLEC11)).

Expression pattern change

Change in timing, level and/or location of gene expression (for example, in protocadherin 11 from the X chromosome to the Y chromosome (PCDH11XY)).

Neofunctionalization

A process by which a genetic change in an allele produces a novel protein function (for example, in double homeobox (DUX) family members).

De novo human gene

A novel gene arising from formerly non-coding DNA (for example, in chronic lymphocytic leukaemia upregulated 1 (CLLU1)).

Human-specific disease

A disease that is present only in the human lineage. A number of diseases are thought to be human-specific (such as Alzheimer's disease and myocardial infarction), but proving that such diseases are not present in other species remains a challenging task.

Gene nurseries

Dynamic regions of the genome that are capable of undergoing rapid evolutionary change owing to a duplication-prone genome architecture and are therefore frequent sites for the production of novel genes by gene duplication.

Hydatidiform mole

An abnormal form of pregnancy in which a non-viable egg, probably the result of an egg missing a nucleus, is fertilized and becomes a mass on the uterine wall. The resultant growing tissue is haploid in nature owing to it having only a paternal genetic contribution.

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O'Bleness, M., Searles, V., Varki, A. et al. Evolution of genetic and genomic features unique to the human lineage. Nat Rev Genet 13, 853–866 (2012). https://doi.org/10.1038/nrg3336

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