L

HoxD complex

J Evx2 Enl Dlx2 Ihh

Figure 4.3

Large-scale duplications in vertebrate genomes

Syntenic regions between vertebrate chromosomes are signs of large-scale duplications or tetraploidization events in the vertebrate lineage. Humans have four Hoxcomplexes, which are flanked by homologs of the Evx, En, Dlx, Hh, and Wntgenes (in syntenic order). Some genes have been lost within the Hox clusters and, presumably, from the flanking regions of each chromosome (e.g., Evx and En genes from chromosome 17). Chromosomes are not to scale and intervening genes are not shown. Source: Redrawn from Postlethwait JH, Yan YL, Gates MA, et al. Nature Genet 1998; 18: 345-349.

related to each other than to any of the engrailed homologs found in more basal vertebrate taxa. Fish engrailed genes have duplicated yet again to create four paralogs—Eng1a, Eng1b, Eng2, and Eng3.

Mapping gene duplication events onto an animalphylogeny

The relative timing of gene duplication events can be mapped onto an animal phylogenetic tree to provide a complete history of the evolution of a gene family. The presence of the same pair of duplicated genes in multiple animals indicates that the gene duplication event preceded the separation of their respective lineages; thus, this event must have predated their last common ancestor.

Continuing with the analysis of vertebrate engrailed genes, it is clear that the engrailed gene was duplicated early in vertebrate evolution, as humans, mice, and chicks have two paralogous engrailed genes (En1 and En2). The engrailed gene phylogeny indicates that one

Human En1 Mouse En1 Chicken En1

Zebrafish Engl

Zebrafish Englb Human En2 Mouse En2 Chicken En2

Zebrafish Eng2

Figure 4.4

Phylogeny of deuterostome engrailed genes

This phylogenetic tree depicts the history of the deuterostome engrailed genes. All of these engrailed genes are homologs, because they share common ancestry. Gene duplication events (indicated by asterisks) have created multiple engrailed genes in higher vertebrates. Humans, mice, and chickens have two genes (Enl and En2) and fish have four genes, compared with the single engrailed gene found in lamprey, amphioxus, and echinoderms. Yellow boxes represent orthologous genes that arose from animal lineage bifurcations. Blue and green boxes indicate paralogous engrailed genes found in the mouse and zebrafish genomes (respectively) that were created by gene duplication.

Source: Redrawn from Force A, Lynch M, Pickett FB, et al. Genetics 1999; 151: 1531-1545.

Zebrafish Eng3

Lamprey Enga Amphioxus En Sea Urchin En

duplication occurred early in the vertebrate lineage after the divergence of lamprey (Fig. 4.5). A second duplication within the fish lineage generated the four engrailed genes found in zebrafish.

One critical step in establishing the relative timing of duplication events in a gene family is the careful choice of one or more outgroups (for example, animal lineages that diverged before a gene duplication) to help determine the ancestral condition for a group of organisms. In the case of engrailed, the identification of a single gene in lamprey and in several other basal deuterostome taxa is consistent with the ancestral deuterostome lineage having had a single engrailed gene.

In practice, decoding the pattern and timing of gene duplication is often more difficult than suggested by this scenario. The resolution of the branching pattern of gene phylogenies is not always definitive and can be consistent with more than one historical path. It can prove difficult to determine with certainty whether members of a gene family arose from a duplication in a common ancestor or from more recent, independent duplications in different animal lineages. The possibility of gene loss also can obscure the timing of a gene duplication event. Without a complete reconstruction of ancestral states, it is difficult to interpret whether

Number of engrailed genes

Figure 4.5

Evolution of engrailed genes in deuterostomes

The engrailed gene duplication events discussed in Figure 4.4 are mapped onto a deuterostome phylogeny. The duplication event that created the En1 and En2 genes of higher vertebrates appears below the divergence of tetrapods and fish, because both of these genes are present in higher vertebrates, but above the lamprey lineage. Other duplication events in the fish lineage created the gene pairs Engla/Englb and Eng2/Eng3, perhaps with a single genome-wide tetraploidization.

Human 2

Mouse

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