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Saving Our Tree HUMAN GENETICS

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Saving Our Tree HUMAN GENETICS HIGHLIGHTS EVOLUTION IN BRIEF Saving our tree HUMAN GENETICS Identification of a gene responsible for familial For several years, evolutionary biolo- Wolff–Parkinson–White syndrome. gists interested in gene flow between species have been investigating and Gollob, M. H. et al. N. Engl. J. Med. 344, 1823–1831 (2001) debating a controversial issue: the hor- Wolff–Parkinson–White (WPW) syndrome is an inherited heart izontal exchange of genes between dis- defect associated with arrhythmia, cardiac arrest and sudden death. tantly related species, its extent and Gollob et al. studied two large families with autosomal-dominant possible adaptive significance. WPW syndrome, and used a positional candidate-gene approach to Horizontal gene transfer (HGT) is an identify the causative gene, which encodes a regulatory subunit of important evolutionary force in appears in a cluster of bacterial AMP-activated protein kinase. This finding should shed light on prokaryotes, as their life cycles facilitate sequences, then the vertebrate gene the mechanisms that lead to heart arrhythmias. the exchange of genes between even was probably horizontally transferred distantly related species. However, this from bacteria. Conversely, if all GENETIC NETWORKS is trickier in multicellular organisms, eukaryotic sequences cluster together, in which the fixation of horizontally then HGT has probably not occurred Ordering genes in a flagella pathway by analysis of transferred genes can only occur if as this grouping is most parsimo- expression kinetics from living bacteria. they are transmitted through the germ niously explained by vertebrates hav- Kalir, S. et al. Science 292, 2080–2083 (2001) line. It was therefore surprising when ing acquired the sequence by descent the International Human Genome through other eukaryotes. All but one The genetic pathway that leads to E. coli flagellar development has Sequence Consortium reported that of the 28 candidate sequences tested been well scrutinized, and the expression of the 14 required 113 genes might have been horizontal- fell into the latter (or similar) category operons divided into three phases. These authors used GFP-tagged ly transferred from bacteria to verte- and therefore do not qualify as HGT genes to study the expression kinetics of the operons in living cells. brates. So surprising, in fact, that sev- events. Further support for the They found a strict, and finely tuned, temporal ordering of gene eral groups set about investigating absence of bacteria-to-vertebrate expression between and within the three phases, reflecting the whether it was true. Their recently HGT also comes from Roelofs et al.’s order in which parts of the flagellum are required. published results argue that it proba- findings that at least 11 of the 113 list- bly isn’t, and that similar sequences ed human genes have homologues in MOUSE MODEL present in humans and bacteria can the primitive eukaryote Dictyostelium. β be explained by descent through The reasons for the original pre- Tissue-specific deletion of Foxa2 in pancreatic cells common ancestry. dictions are varied. Perhaps non- results in hyperinsulinemic hypoglycemia. To qualify as a HGT event, a vertebrate eukaryotic orthologues Sund, N. J. et al. Genes Dev. 15, 1706–1715 (2001) sequence must satisfy two criteria: it were not actively searched for or were Human familial hyperinsulinism is characterized by increased must be present in two species and not found because too few taxa were insulin secretion and hypoglycaemia. Sund et al. have now created be absent from any evolutionary sampled, or those that were had been a mouse model of this disorder by knocking out Foxa2 in a intermediate species (in this partic- affected by gene loss. pancreatic β-cell-specific manner. Mutants show many features of ular case, from non-vertebrate There are therefore many plausi- the disorder, such as very low glucose and high insulin blood levels. eukaryotes). ble biological explanations, other These effects might be mediated by the downregulation of a K+ By comparing the protein than HGT, for why two species channel that is normally involved in insulin secretion — a sequences of several taxa, Salzberg et might share a similar sequence — potentially valuable insight into the pathology of hyperinsulinism. al. found that only about 40 of the as things stand, the exciting possi- claimed HGT candidate sequences bility that a bacteria-to-vertebrate EVOLUTION were exclusively shared by humans HGT event has occurred seems to and bacteria, arguing against their be fading fast. Haplotype diversity and linkage disequilibrium at human direct transfer from bacteria to Tanita Casci G6PD: recent origin of alleles that confer malarial humans. resistance. Phylogenetic analysis is the most References and links Tishkoff, S. A. et al. Science 21 June 2001 (10.1126/science.1061573) objective way to establish whether a ORIGINAL RESEARCH PAPERS Salzberg, S. L. gene has been transferred to verte- et al. Microbial genes in human genome: lateral Low activity alleles of glucose-6-phosphate dehydrogenase brates by horizontal transmission transfer or gene loss? Science 292, 1903–1906 (2001) | Stanhope, M. J. et al. Phylogenetic (G6PD), which is required for glucose metabolism and oxidative from bacteria. Stanhope et al. rea- analyses do not support horizontal gene stress responses, are maintained in human populations that inhabit soned that a real HGT gene should be transfers from bacteria to vertebrates. Nature malarial regions, possibly because they confer partial resistance to 411, 940–944 (2001) | Roelofs, J. et al. more similar to sequences of the Genes lost during evolution. Nature 411, malaria. To investigate this, Tishkoff et al. analysed two G6PD donor lineage than to other 1013–1014 (2001) haplotypes and found evidence that they evolved independently FURTHER READING Andersson, J. O. et al. sequences, a prediction that could be Are there bugs in our genome? Science 292, several thousand years ago. Their results indicate that malaria has phylogenetically tested: if, in an evolu- 1848–1850 (2001) only had an impact on human evolution since the introduction of tionary tree, a vertebrate sequence WEB SITE Steven Salzberg’s home page agriculture, ~ 10,000 years ago. NATURE REVIEWS | GENETICS VOLUME 2 | AUGUST 2001 | 571 © 2001 Macmillan Magazines Ltd.
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