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Giraffe Genome Sequence Reveals Clues to Its Unique Morphology and Physiology

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Giraffe Genome Sequence Reveals Clues to Its Unique Morphology and Physiology

Morris Agaba et al. Nat Commun.

Abstract

The origins of giraffe's imposing stature and associated cardiovascular adaptations are unknown. Okapi, which lacks these unique features, is giraffe's closest relative and provides a useful comparison, to identify genetic variation underlying giraffe's long neck and cardiovascular system. The genomes of giraffe and okapi were sequenced, and through comparative analyses genes and pathways were identified that exhibit unique genetic changes and likely contribute to giraffe's unique features. Some of these genes are in the HOX, NOTCH and FGF signalling pathways, which regulate both skeletal and cardiovascular development, suggesting that giraffe's stature and cardiovascular adaptations evolved in parallel through changes in a small number of genes. Mitochondrial metabolism and volatile fatty acids transport genes are also evolutionarily diverged in giraffe and may be related to its unusual diet that includes toxic plants. Unexpectedly, substantial evolutionary changes have occurred in giraffe and okapi in double-strand break repair and centrosome functions.

Figures

Figure 1
Figure 1. Divergence of giraffe and okapi from a common ancestor.
Using the average pairwise synonymous substitution divergence (dS) estimates between giraffe, okapi and cattle as calibrated by the pecoran common ancestor (27.6 mya), the divergence of giraffe and okapi from a common ancestor is estimated to be 11.5 mya. Okapi image adapted from a photograph by Raul654.
Figure 2
Figure 2. Network analysis of GO biological process of giraffe MSA genes.
Seventy genes were identified that exhibited MSAs based on amino acid sequence divergence as evaluated by neighbour-joining phylogenetic analysis of mammalian orthologous proteins, enrichment of nonsynonymous substitutions, unique amino acid substitutions at sites otherwise fixed in mammals, substitutions predicted to cause functional changes by Polyphen2 analysis and substitutions under positive selection. Cluster analysis was performed on the set of 70 giraffe MSA genes based on GO Biological Process using Cytoscape 3.0 (ref. 68).
Figure 3
Figure 3. Giraffe genes and pathways exhibiting extraordinary divergence and patterns of amino acid substitutions.
(a) Giraffe FGFRL1 contains seven amino acid substitutions that are unique at fixed sites in other mammals and/or are predicted by Polphen2 analysis to alter function (upper panel). Human reference is shown, which is identical to cattle and okapi in this segment. The unique giraffe substitutions occur in the FGF-binding domain region flanking the N-terminal cysteine (asterisk) of the Ig-III loop (lower panel). Red bracket in lower panel corresponds to the sequence in the upper panel. The extracellular structure of FGFRL1 (left) is the same as a prototypical FGF receptor (FGFR, right) but lacks the cytoplasmic C-terminal tyrosine kinase domains seen in FGFR and instead contains a zinc-binding domain. (b) Giraffe FOLR1 contains seven substitutions that each show evidence of positive selection (P<0.05) by the branch-site model. Two of the positive selected sites (PSG), P48S and E222K, are also unique substitutions at fixed sites and Polyphen2 (PP2) analysis predicts them to alter function. P48S is within β-sheet-1 that forms part of the folic acid-binding pocket. The FOLR1 protein forms a globular structure maintained by overlapping disulfide bridges between 16 cysteine residues (red) and tethered to the plasma membrane at S233 by a Gpi anchor. The unique substitution in giraffe, G234Q, immediately adjacent to the Gpi anchor site may alter the anchor site or the rate of its formation. (c) Genes encoding key enzymes in butyrate metabolism and downstream mitochondrial oxidative phosphorylation pathways have diverged in giraffe including the monocarboxylate transporter (MCT1), acyl-coenzyme A synthetase-3 (ACSM3), short-chain specific acyl-CoA dehydrogenase (ACADS), NADH dehydrogenase (ubiquinone) 1β subcomplex subunit 2 (NDUFB2) and succinate dehydrogenase [ubiquinone] iron-sulfur subunit (SDHB). ACSM3 and ACADS are located in the mitochondrial matrix where as NDUFA2, NDUFB2 and SDHB are located in the mitochondrial inner membrane. In addition to being present in the rumen epithelial cells, MCT1 is highly expressed in the heart, skeletal muscle and the nervous system where it acts to transport volatile fatty acids (VFAs) and lactate. (d) Double-strand break repair genes exhibit divergence in giraffe and/or okapi. The mediator of DNA-damage check point 1 (MDC1) binds phosphorylated H2AX, which mark DNA double-strand break, and serves as scaffold to recruit the MRN DNA repair complex composed of NBS1, MRE11 and RAD50 (upper panel). The giraffe and okapi MDC1 gene exhibits a 264 amino acid deletion that removes part of the SDT region that harbours two critical CK2 phosphorylation sites (lower panel). These two phosphorylation sites are among multiple sites that regulate the interaction of MDC1 and NBS1 essential for the recruitment of the MRN complex to double-strand breaks.
Figure 4
Figure 4. Gene cluster analysis of genes that exhibit evidence of adaptive evolution in giraffe.
Developmental and physiological regulatory genes in giraffe that exhibit adaptive evolution are enriched in skeletal, cardiovascular and neural functions. The MSA genes that are not known to be related to the regulation of skeletal, cardiovascular, or neural development are listed (right box).

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