Comparing the Human and Fish Genomes

Abstract

Comparing human and fish genomes has been proven useful to understand vertebrate evolution. To demonstrate this, two major questions and related findings are addressed here. In 1970, based on limited observations, Ohno postulated that whole genome duplication events took place in early vertebrates and were essential to increasing complexity of vertebrates over the past 600 My. For providing conclusive support to Ohno's hypothesis, comparative genomics of the fish and human genomes was indispensable. Another question is whether deoxyribonucleic acid (DNA) sequence variation might reflect germ line genetic activity, underlying chromatin structure and DNA methylation. Analysis of the medaka fish and human genomes uncovered two important properties. Nucleosome positioning is correlated with periodic sequence variation downstream of transcription start sites in germ line cells, and genome‐wide genetic variations are highly correlated with proximal DNA methylation patterns. These findings suggest the potential for genetic activity (transcription), chromatin structure and DNA methylation to contribute to moudling the DNA sequence on an evolutionary timescale.

Key Concepts:

  • In 1970, based on limited observations, Ohno postulated that whole genome duplication events took place in early vertebrates and were essential to increasing complexity of vertebrates over the past 600 My.

  • Comparative genomics of the fish and human genomes was indispensable to provide conclusive support to Ohno's hypothesis.

  • Nucleosome positioning is correlated with periodic sequence variation downstream of transcription start sites in germ line cells.

  • Genome‐wide genetic variations are highly correlated with proximal DNA methylation patterns.

  • Nakatani et al. suggest a contrast between the slow karyotype evolution after the second WGD and the rapid, lineage‐specific genome reorganisations that occurred in the ancestral lineages of major taxonomic groups such as teleost fishes, amphibians, reptiles, and marsupials.

Keywords: comparative genomics; evolution; vertebrate genomes; DNA methylation; genetic variation; transcription start site; single nucleotide polymorphism

Figure 1.

(a) Vertebrate karyotype evolution. The left picture shows the phylogenetic tree of vertebrates. The phylogenetic positions of the 2R WGD events relative to the jawless vertebrate divergence remain unresolved (Putnam et al., ; Kuraku et al., ). The right column displays the distribution of chromosome numbers in individual lineages. The data were obtained from the Animal Genome Size Database: http://www.genomesize.com. (b) A model of genome evolution involving the WGD events. (c) Paralogues shared in common between chromosomes S1 and S2 in (b) are represented by dot plots. (d) Dots enclosed in boxes represent paralogous blocks. (e) Similarly, dots show paralogues among S3, S4, S5 and S6.

Reproduced with permission from Nakatani et al.2007. © Cold Spring Harbor Laboratory Press.
Figure 2.

(a) Reconstruction of the ancestral genome before the 2R WGD. For simplicity, it is supposed that the ancestral chromosome had 10 genes. The 2R WGD produced ohnologues, represented by blue dots along the diagonal line in the triangular dot plot, in the duplicated chromosomes. (b) Chromosome breaks and inversions may have altered the order of ohnologues on the sister chromosomes. (c) In the course of early vertebrate genome evolution, the ancestral gene order was disrupted by numerous inversions, resulting in scattered ohnologue dots. (d) Eventually, CVL blocks were distributed across several human chromosomes through intensive interchromosomal rearrangements. Steps a–d illustrate a typical model of genome evolution involving the 2R WGD. In the next step, real human genome data are handled. (e) This is a real instance of the dot plot in (d). CVL blocks were ordered from the human chromosomes 1 to X and ohnologues shared among these CVL blocks were plotted. (f) This corresponds to the state in (c). The CVL blocks were reordered in such a way that paralogous CVL blocks were grouped so that each group represented one ancestral vertebrate chromosome. (g) This state corresponds to that in (b). The CVL blocks within individual vertebrate groups were further reordered to obtain ancestral gnathostome subgroups (namely, chromosomes), which were duplicated from a single ancestral vertebrate chromosome by the 2R WGD events. The partition of subgroups optimises the significance. (h) The vertebrate group A was decomposed into four gnathostome subgroups by statistical analysis, indicating that the ancestral chromosome underwent 2R WGD.

Reproduced with permission from Nakatani et al.2007. © Cold Spring Harbor Laboratory Press.
Figure 3.

Reconstruction of ancestral osteichthyan and amniote protochromosomes. The number of protochromosomes ranges from 10 to 13, depending on the choice of two alternative models that assume fissions or fusions between the two WGD events. The figure illustrates the scenario in which only fissions took place. The 10 reconstructed protochromosomes in the vertebrate ancestor shown at the top are assigned distinct colours, and their daughter chromosomes in the gnathostome ancestor are distinguished by the respective vertical bars. In the genomes of the osteichthyan, teleost and amniote ancestors and human, chicken and medaka genomes, genomic regions are assigned colours and vertical bars that represent correspondences of individual regions to the protochromosomes in the gnathostome ancestor from which respective regions originated. In addition, for better understanding, each gnathostome protochromosome is assigned a unique identifier. These identifiers are used to emphasise the origins of extant and ancestral chromosomes. Unassigned blocks are shown in the rightmost chromosome labelled ‘Un’ in the osteichthyan and amniote ancestors.

Reproduced with permission from Nakatani et al.2007. © Cold Spring Harbor Laboratory Press.
Figure 4.

Teleost genome evolution. (a) The figure depicts a model of the distribution of ancestral chromosome segments in the human, zebrafish, medaka and Tetraodon genomes. Thirteen reconstructed ancestral chromosomes are represented by the coloured bars, and the genomic regions originating in the ancestral chromosomes have the same colour coding. Major rearrangements are represented by arrows and lineage‐specific small‐scale translocations by dotted arrows. The dotted box for the zebrafish indicates that most parts of the chromosome were lost through extensive translocations. (b) The basis of the logic of deducing the teleost genome evolution is shown by illustrating how ancestral chromosome b is inferred. (c) Dots represent synteny blocks between the medaka and Tetraodon chromosomes.

Reproduced with permission from Kasahara et al.2007. © Nature Publishing Group.
Figure 5.

Nucleosome positioning, methylation patterns and substitution/indel rates in the inbred medaka strains, Hd‐rR and HNI. (a) The x‐axis shows the distance from the representative TSSs in the medaka (Hd‐rR) genome. Colour key shows rates: blue line, mismatch mutation (substitution) rate; red line, indel mutation rate; and grey line, rate of indels of length 1 bp. For smoothing of lines, a running average over a 23‐bp window (one full turn of the helix in each direction) is depicted. (b) The average local dyad positioning score has local minima at positions +200, +400, +600 and +800 bp from the TSSs, which suggests the presence of phased arrays of nucleosomes every ∼200 bp downstream of the TSS. (c) SNP rates in hyper‐ and hypomethylated CpG blocks in the reference human genome (hg19). The difference in SNP rates was significant in the entire genome (p<10E–566 by two‐proportion z‐test), in intergenic regions (p<10E–305), in exons (p<10E–29) and in introns (p<10E–151). (d) Methylation level and SNP distribution in the homologous regions of the human and medaka genomes where gene RPS13 is coded. (e–f) Comparisons of the methylation patterns in Hd‐rR and HNI. The vertical and horizontal axes indicate methylation level. The heat map uses logarithmic coordinates and presents the number of corresponding CpG site blocks. Conserved hypermethylated and hypomethylated patterns between the two strains were dominant, except for a small number of hot spots observed in the differentially methylated regions (differences in methylation level ≥0.5). (g) Comparison of the methylation patterns in blastulae and testes in Hd‐rR. (h) SNP rates in hypo‐, hyper‐, and strain‐differentially methylated regions in medaka blastulae grouped by the entire genome, intergenic regions, exons and introns. The differences between SNP rates of hypo‐ and hypermethylated regions were remarkable: p<10E–2170 (genome), p<10E–2170 (intergenic regions), p<10E–113 (exons) and p<10E–589 (introns), according to two‐proportion z‐test. Furthermore, the differences between SNP rates of strain‐differentially and hypermethylated regions were also significant. (i) Dinucleotide substitution rates in the whole medaka genome, intergenic regions, exons and introns in CpG site blocks with various methylation states. Colour key presents mutation rates: blue for hypermethylated (methylation level ≥0.8 in both strains); red for hypomethylated (methylation level ≤0.2 in both strains); and green for strain‐differentially methylated (difference in methylation level between the two strains ≥0.5) in blastulae. The axes in each radar chart represent substitution rates of individual dinucleotides. Each dinucleotide shows the same substitution rate as its reverse complementary dinucleotide. Significant differences between substitution rates in hypo‐ and hypermethylated regions were observed for all dinucleotides, and the p‐values according to two‐proportion z‐test were p<10E–441 (genome), p<10E–263 (intergenic regions), p<10E–15 (exons) and p<10E–69 (introns).

Reproduced with permission from Qu et al.2012. © Cold Spring Harbor Laboratory Press.
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Nakatani, Yoichiro, Qu, Wei, and Morishita, Shinichi(Sep 2013) Comparing the Human and Fish Genomes. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0021004.pub2]