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  • Review Article
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Dissecting evolution and disease using comparative vertebrate genomics

Nature Reviews Genetics volume 18, pages 624–636 (2017)Cite this article

Subjects

Key Points

  • The insight gained through comparative genomics is markedly increasing as novel sequencing technologies are developed and become more affordable. Different technologies, data types and quality can be used to ask biological questions within or across species.

  • Genome annotation, incorporating coding genes, non-coding RNAs, transcription factor-binding sites, chromatin marks and more, are key to understanding genome evolution and disease. Many of these features are shared across species.

  • Genotype–phenotype correlations can be used to understand the genetic basis of numerous traits and diseases. These can be studied both on the individual, population or species level.

  • Tools and resources for genome annotation and trait mapping have made it possible to identify disease genes in many domestic animals. This information can also be used to guide the search for human disease-associated genes.

  • Low-pass population data has been successfully implemented to find natural genetic adaptations to salinity, high altitude and diet. Mutation types vary from coding to non-coding and from point mutations to structural variants.

  • Analysis of large numbers of mammals, birds or fish will enable the detection of constraint (a sign of function) as well as positive selection across clades. Convergent evolution, in which different mutations in the same genetic loci are responsible for specific phenotypic adaptation, is apparent across many lineages, including the red and giant pandas.

Abstract

With the generation of more than 100 sequenced vertebrate genomes in less than 25 years, the key question arises of how these resources can be used to inform new or ongoing projects. In the past, this diverse collection of sequences from human as well as model and non-model organisms has been used to annotate the human genome and to increase the understanding of human disease. In the future, comparative vertebrate genomics in conjunction with additional genomic resources will yield insights into the processes of genome function, evolution, speciation, selection and adaptation, as well as the quantification of species diversity. In this Review, we discuss how the genomics of non-human organisms can provide insights into vertebrate biology and how this can contribute to the understanding of human physiology and health.

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Figure 1: A snapshot of vertebrate genome sequencing projects.
Figure 2: Designing a sequencing project.
Figure 3: A case study in phenotypic adaptation: high altitude and EPAS1.
Figure 4: Comparative genomics for convergent evolution analyses.

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Acknowledgements

J.R.S.M. was supported by the Swedish Research Council, FORMAS (221-2012-1531). K.L.-T. was supported by the Swedish Research Council, European Research Council (ERC) Starting Grant and Knut och Alice Wallenberg Foundation.

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Authors and Affiliations

  1. Department of Medical Biochemistry and Microbiology, Science for Life Laboratory, Uppsala University, Box 582, Uppsala, 75123, Sweden

    Jennifer R. S. Meadows & Kerstin Lindblad-Toh

  2. Broad Institute of Massachusetts Institute of Technology and Harvard, 415 Main Street, Cambridge, 02142, Massachusetts, USA

    Kerstin Lindblad-Toh

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Correspondence to Kerstin Lindblad-Toh.

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PowerPoint slides

Glossary

Reference genome

A high-quality species genome onto which other information is projected, such as genes, polymorphisms and elements of gene regulation.

Bacterial artificial chromosome

(BAC). Approximately 200,000 bp of sequence that has been cloned into a bacterial vector and can then be amplified and sequenced.

Whole-genome shotgun sequencing

The genome is shattered into smaller pieces and sequenced, originally with Sanger technology.

Sanger sequencing

An old standard type of sequencing in which the four bases are labelled with four fluorophores of different colours. It results in ~600 bp reads and was the methodology used for the human genome project.

High-quality draft genome assemblies

A form of genome assembly that has both long contigs (stretches of uninterrupted sequence, many kb in length) and supercontigs (structures of sequence hanging together but including smaller gaps) in the Mb range.

Haplotype blocks

Regions of the genome that are inherited together without recombination. These are characterized by high linkage disequilibrium.

Vertebrate model species

Vertebrate species that are studied to understand the biology or phenotype in another species.

Non-model organisms

Organisms that are examined to offer insight into themselves rather than principally studied to understand another trait, for example, human health.

Short-read sequencing

(SRS). Short-read technologies, such as Illumina, generate continuous sequence length of 100–250 bp.

Long-read sequencing

(LRS). Strategies such as PacBio's single-molecule real-time (SMRT) generate continuous sequence length in the order of many kilobases. Over time, these technologies will go down in price and will probably be the methods of choice.

Haplotypes

Versions of a gene or part of a gene, including several variants that are inherited together.

Chromosome interaction mapping

A methodology to analyse the 3D organization of chromatin. Looping can be functional, for example, bringing enhancers into contact with distal promoters.

Single-nucleotide polymorphisms

(SNPs). When a position in the genome can have two or more alleles. Biallelic markers are used to look for association of one allele (gene version) with disease.

RNA sequencing

(RNA-seq). The sequencing of all mRNA transcripts from a cell or tissues.

Histone marks

Histones are proteins that package DNA into units. Histone marks indicate where chromatin is open or closed and provide insights into genome regulation; for example, histone 3 lysine 27 acetylation (H3K27ac), is associated with active enhancers.

Adaptation

A trait that has changed to enable a species to function under certain circumstances or in a specific environment.

Domestication

A complex process partly driven by human selection of standing natural variation.

Convergent evolution

The independent evolution of similar features in multiple species of different lineages.

Pooled genome sequence strategies

Several individuals and/or samples can be sequenced together as a group, either with or without barcode labelling to facilitate multiplexing.

Representative genome assembly approaches

When multiple individual genomes are sequenced from a species, the best is selected as a reference genome for that organism.

N50 contig

A statistic used to illustrate genome quality. Genomes are constructed of multiple contigs (a segment of the genome assembly that contains no gaps), each with different lengths. N50 size is the shortest sequence length containing half of the genome sequence.

Long-range contiguity

The linking of large, megabase-sized genomic regions in order to create large continuous lengths of sequence data.

Conserved synteny

The similarity of gene order in large regions of related (and distant) species.

Microchromosomes

Typical in some birds and lizards, these chromosomes are less than 20 Mb in size.

Selective sweep

A region of the genome where there is little to no population-level variation, as one haplotype with favourable alleles has become more common than other variants.

Hybridization

The mating of two different species or populations, resulting in equal proportions of genetic material from both parents.

Introgression

Gene flow from one species into the gene pool of another by the repeated backcrossing of a hybrid with one of its parental species.

Integrated haplotype homozygosity score

(iHS). A method to calculate the amount of genetic similarity across regions in a species or population. High homozygosity suggests selection to be active on that region.

SNP genotyping arrays

A method to genotype predefined single-nucleotide variants distributed across the genome of the species under study. For humans, single-nucleotide polymorphism (SNP) arrays typically have millions of variants, whereas in dogs, hundreds of thousands of SNPs are used for genome-wide association mapping.

Topologically associating domains

(TADs). Regions of the genome packaged together in 3D space, most often containing one or a few genes and their regulatory signals. Genomic interactions within TADs are more frequent than those across TAD borders.

Microevolution

Changes in allele frequencies that happen within a population in a fairly short time span. This can be due to positive selection or drift.

Macroevolution

Changes in allele frequencies that happen between species over a longer time period. This can be due to positive selection or drift.

Silent changes

Changes in DNA sequence without biological consequence.

Neutral sites

Positions in DNA that are not functional and hence are free to mutate randomly.

Conserved non-coding elements

(CNEs). Regions of the genome that are not coding for proteins, but are similar in many species, suggesting a role for these elements in genome regulation.

Transposable elements

Mobile DNA sequences, similar to viruses, that can 'jump' around in the genome and integrate in new locations. These sequences can affect gene expression or give rise to novel regulatory elements.

Positive selection

The force that makes certain genetic positions change in a certain favourable direction.

Accelerated regions

Regions of the genome that are typically conserved across species, but where novel changes have happened in one or more related species. This suggests that the region is under positive selection for the novel variant (or variants).

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Meadows, J., Lindblad-Toh, K. Dissecting evolution and disease using comparative vertebrate genomics. Nat Rev Genet 18, 624–636 (2017). https://doi.org/10.1038/nrg.2017.51

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