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Part II
STRUCTURE AND FUNCTION OF THE HUMAN GENOME

The first published reports of the complete nucleotide sequence of a human genome appeared near the turn of the 21st century (Lander et al., 2001; Venter et al., 2001), and the full sequence of a chimpanzee genome was unveiled soon thereafter (Chimpanzee Sequencing and Analysis Consortium, 2005). Overall, humans and chimpanzees proved to be about 99% identical in the nucleotide regions they share (which include most of the genome and essentially all genes). Thus, somewhere within that “other 1%” of the nucleotide sequence must reside all of the genetic changes that biologically differentiate humans from our closest living relatives. The “smallness” of the genetic divergence can be deceptive; a 1% sequence difference means that the human and chimpanzee genomes differ at about 30,000,000 among their 3 billion pairs of nucleotides. A monumental challenge for the field of evolutionary genetics is to pinpoint the specific genomic alterations that causally underlie (and precisely how so?) various unique features that make us human.

In Chapter 6, Ajit Varki describes an apparent “hotspot” in human genomic evolution, involving multiple loci that encode or regulate the expression of sialic acids (Sias) and the receptors that recognize them. The Sias are ubiquitous molecules that “decorate the canopy of the glycan forest” on cell surfaces and thereby play several key roles in human health and disease, for example by serving as cell-surface signals for “self” recognition in the vertebrate immune system, or as cell-surface targets for the extrinsic receptors of many pathogens. By comparing the suite of human sialic acids and their associated binding proteins against those of



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Part II STRUCTURE AND FUNCTION OF THE HUMAN GENOME T he first published reports of the complete nucleotide sequence of a human genome appeared near the turn of the 21st century (lander et al., 2001; venter et al., 2001), and the full sequence of a chimpan- zee genome was unveiled soon thereafter (Chimpanzee sequencing and Analysis Consortium, 2005). overall, humans and chimpanzees proved to be about 99% identical in the nucleotide regions they share (which include most of the genome and essentially all genes). Thus, somewhere within that “other 1%” of the nucleotide sequence must reside all of the genetic changes that biologically differentiate humans from our closest living relatives. The “smallness” of the genetic divergence can be deceptive; a 1% sequence difference means that the human and chimpanzee genomes differ at about 30,000,000 among their 3 billion pairs of nucleotides. A monumental challenge for the field of evolutionary genetics is to pinpoint the specific genomic alterations that causally underlie (and precisely how so?) various unique features that make us human. in Chapter 6, Ajit varki describes an apparent “hotspot” in human genomic evolution, involving multiple loci that encode or regulate the expression of sialic acids (sias) and the receptors that recognize them. The sias are ubiquitous molecules that “decorate the canopy of the gly - can forest” on cell surfaces and thereby play several key roles in human health and disease, for example by serving as cell-surface signals for “self” recognition in the vertebrate immune system, or as cell-surface targets for the extrinsic receptors of many pathogens. By comparing the suite of human sialic acids and their associated binding proteins against those of 0

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0 / Part II nonhuman primates, varki details the molecular bases and the putative functional consequences of more than 10 evolutionary genetic changes that seem to be specific to the human lineage. overall, varki’s analyses reveal multifaceted and oft-unexpected roles for cell-surface molecules in human biology and evolution. The sialic acid story also has broader evo - lutionary ramifications. For example, it implies that evolutionary “arms races” between hosts and pathogens can promote a form of “molecular mimicry” whereby different microorganisms convergently “reinvent” the use of sias to help mask themselves from the surveillance of vertebrate immune systems. The sias system also illustrates the profound challenges as well as the opportunities that likely will attend many such attempts to dissect other complex structural and functional components of human genome evolution. Conventionally, “the human genome” refers to the full suite of DnA within the cellular nucleus. however, the nuclear genome has a diminu- tive partner—mitochondrial (mt) DnA—housed in the cellular cytoplasm. The prototypical human mitochondrial genome is only 16,569 base pairs in length (roughly a half-million-fold smaller than each nuclear genome), but what mtDnA lacks in size it more than makes up for in terms of copy num- ber (thousands of mtDnA molecules reside in a typical somatic cell) and functional significance. Proteins and rnAs coded by the mitochondrial genome contribute critically to mitochondrial operations, which provide the cell with its chemical energy. The first complete sequence of human mtDnA was published 30 years ago (Anderson et al., 1981) and since then this “other” genome has become a model system for genealogical reconstructions of human demographic history (Cann et al., 1987) as well as for mechanistic appraisals of genomic structure and function in relation to human health (Wallace, 2005; McFarland et al., 2007). These topics have been thoroughly reviewed elsewhere, but in Chapter 7, Douglas Wallace uses such informational backdrop as a springboard to launch a bioener- getic hypothesis that ascribes a central role for energy flux in generating and maintaining complex biological structures such as the human brain. Wallace envisions a cyclical evolutionary process in which complex adap - tations arise from a synergy between the information-generating power of energy flow and the information-accumulating capacity of selection- winnowed DnA. Under this evolutionary scenario, bioenergetic genes (notably those contributing to mitochondrial function) play key roles. The ongoing genomics revolution in biology that began little more than decade ago is opening new windows not only to the genes that make us human but also to the nature and significance of genetic differences between extant human populations now living in different geographical regions of the planet. As a part of this global monitoring effort by the sci - entific community (rosenberg et al., 2002; Frazer et al., 2007), Katarzyna

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Structure and Function of the Human Genome / 0 Bryc and others associated with the laboratory of Carlos Bustamante provide, in Chapter 8, a detailed case study involving mostly hispanic/ latino populations in Central and south America. The authors compile and analyze genotypic information for several thousand individuals at several tens of thousands of snPs (single-nucleotide polymorphisms) scattered across the two human genomes (nuclear and mitochondrial). The results reveal a complex genetic signature of recent sex-biased admix- ture superimposed on a potentially ancient substructure involving source populations of native American, european, and West African ancestry. in addition to illuminating the genealogical heritage of particular human populations, genomic surveys of this sort, when interpreted in combina- tion with detailed epidemiological data, should also be helpful in studies of the spatial distributions and evolutionary-genetic etiologies of particu - lar human heritable diseases. in Chapter 9, nina Jablonski and George Chaplin show how, even in the age of genomics, much can still be learned about adaptive human evolution from comprehensive geographical analyses of phenotypes, in this case involving the most obvious of all human polymorphisms: skin pigmentation. Although the precise mechanistic action of the full suite of pigmentation genes underlying human skin-color variation remains incompletely known, the authors erect a compelling adaptationist scenario for why humans generally evolved dark skins near the equator and depig- mented but tannable skins at intermediate and higher latitudes. This strik- ing latitudinal pattern appears to reflect selection-mediated responses to two distinct challenges related to exposure to ultraviolet radiation (Uvr), major forms of which (UvA and UvB) vary predictably with latitude and season. in the tropics, where UvA is high year-round, dark pigmentation tends to be selectively advantageous because it protects the body against damaging Uvr exposure. At higher latitudes, where UvB levels gener- ally are lower and peak only once per year, natural selection has tended to favor light but tannable skin that can capture UvB for the cutaneous production of vitamin D, which otherwise must come from a suitable diet. As detailed by Jablonski and Chaplin in their opening comments, this modern understanding of skin color variation in humans is strikingly different not only from some of the racially prejudiced ideas formerly in vogue, but also from the sexual-selection hypothesis for skin pigmentation favored by Darwin in The Descent of Man. Before Darwin, most scientists as well as theologians accepted what seemed obvious: that divine intervention must have underlain nature’s design. The traditional “argument from design” traces back at least to the classical Greek philosopher socrates more than 400 BC [see sedley (2008)], and it was expressed again in a thoughtful treatise entitled Natural Theol- ogy by the reverend William Paley (1802). Darwin later recalled in his

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0 / Part II autobiography [see Barlow (1958)] that Paley’s logic “gave me as much delight as did euclid” and that it was the “part of the Academical Course [at the University of Cambridge] which . . . was the most use to me in the education of my mind.” Darwin himself was a natural theologian when he boarded the Beagle in 1831 on what would be a fateful voyage into previ- ously uncharted scientific waters. Darwin’s discoveries were revolution - ary for philosophy and theology as well as science because they identified a nonsentient directive agent (natural selection) that apparently could craft complex and beautiful biological outcomes that otherwise would be interpreted as direct handiworks of God. in Chapter 10, John Avise asks whether the human genome displays the kinds of artistry of molecular design that natural theologians might wish to claim as definitive proof for ex nihilo craftsmanship by a caring and omnipotent Deity (Behe, 1996). To the contrary, modern genetic and biochemical analyses have revealed, unequivocally, that the human genome is replete with mistakes, waste, dead-ends, and other molecular flaws ranging from the subtle to the egregious with respect to their negative impacts on human health (Avise, 2010). These are the kinds of biological outcomes that are expected from nonsentient evolutionary processes, but surely not from an intelligent designer. Avise argues, nevertheless, that theologians should welcome rather than disavow these genomic discoveries. The evolutionary sciences can help to emancipate mainstream religions from the age-old theodicy dilemma (the theological “problem of evil”) and thereby return religious inquiry to its rightful realm—not as the secular interpreter of biological minutiae of our physical existence, but rather as a respectable counselor on grander philosophical matters that have always been of “ultimate con - cern” (Dobzhansky, 1967) to theologians, and to humanity.