Revisiting an Old Riddle: What Determines Genetic Diversity Levels within Species?

Understanding why some species have more genetic diversity than others is central to the study of ecology and evolution, and carries potentially important implications for conservation biology. Yet not only does this question remain unresolved, it has largely fallen into disregard. With the rapid decrease in sequencing costs, we argue that it is time to revive it.What evolutionary forces maintain genetic diversity in natural populations? How do diversity levels relate to census population sizes (Box 1)? Do low levels of diversity limit adaptation to novel selective pressures? Efforts to address such questions spurred the rise of modern population genetics and contributed to the development of the neutral theory of molecular evolution—the null hypothesis for much of evolutionary genetics and comparative genomics [1]–[3]. Yet these questions remain wide open and, for close to two decades, have been neglected [4]. Most notably, little progress has been made to resolve a riddle first pointed out 40 years ago on the basis of allozyme data: the mysteriously narrow range of genetic diversity levels seen across taxa that vary markedly in their census population sizes [5]. This gap in our understanding is glaring, and may hamper efforts at conservation (e.g., [6]).

Box 1. Glossary

Allozymes: Allelic variants of a protein, often detected by differences in gel electrophoresis. Balancing selection: Natural selection that maintains variation longer than expected from genetic drift alone. Census population size: The actual number of individuals in a population; methods to estimate this number vary depending on the species and may involve aerial, transect, or capture/recapture counts. Diversity levels: The measure used here is the probability that a pair of randomly chosen haplotypes differ at a site. Effective population size: The size of an idealized population with some of the same properties as the actual one, e.g., the same rate of genetic drift. Under simplifying assumptions, notably a constant population size and no population structure, this parameter can be estimated from observed diversity levels, given an independent estimate of the mutation rate. Fluctuating selection: When the fitness of an allele changes over time or over space. Genetic draft: A dramatic loss of genetic variation due to strong, frequent selection at nearby sites [8]. Genetic drift: In a finite population, the loss of genetic variation due to the random sampling of gametes at each generation. Local adaptation: Adaptation to a particular environment that is not shared by the entire species. Nearly neutral theory of molecular evolution: A modification of the neutral theory, in which many mutations are slightly deleterious, rather than strictly neutral or strongly deleterious [75]. Neutral theory of molecular evolution: The theory that most genetic variation seen within populations and between species is neutral, and most mutations are either neutral or strongly deleterious [11]. Panmixia: Random mating among individuals, and hence no population structure. Phylogenetically independent contrasts: A statistical method that allows one to compare properties of species controlling for their evolutionary relationship. Purifying (negative) selection: Natural selection that favors the common, fitter allele against rare, deleterious alleles. Selection at linked sites: Selection at sites linked to the locus under consideration, which can affect the population dynamics of alleles at that locus. Silent sites: A general term for synonymous, intronic, and intergenic sites—all sites at which mutations do not change an amino acid. Variation-reducing selection: Selection that leads to a decrease in diversity at linked sites.With the recent technological revolution in sequencing, the data needed to address questions about the determinants of genetic diversity levels are now within reach. As a first step towards reviving these questions, we compile existing estimates of nuclear sequence diversity. These data are highly preliminary, but they underscore how little is known about the narrow span of diversity levels across species or why some species maintain more genetic variation than others [5],[7],[8], and they offer a glimpse of trends that may be worth pursuing.     

The role of alpha 6 integrin in prostate cancer migration and bone pain in a novel xenograft model

Of the estimated 565,650 people in the U.S. who will die of cancer in 2008, almost all will have metastasis. Breast, prostate, kidney, thyroid and lung cancers metastasize to the bone. Tumor cells reside within the bone using integrin type cell adhesion receptors and elicit incapacitating bone pain and fractures. In particular, metastatic human prostate tumors express and cleave the integrin A6, a receptor for extracellular matrix components of the bone, i.e., laminin 332 and laminin 511. More than 50% of all prostate cancer patients develop severe bone pain during their remaining lifetime. One major goal is to prevent or delay cancer induced bone pain. We used a novel xenograft mouse model to directly determine if bone pain could be prevented by blocking the known cleavage of the A6 integrin adhesion receptor. Human tumor cells expressing either the wildtype or mutated A6 integrin were placed within the living bone matrix and 21 days later, integrin expression was confirmed by RT-PCR, radiographs were collected and behavioral measurements of spontaneous and evoked pain performed. All animals independent of integrin status had indistinguishable tumor burden and developed bone loss 21 days after surgery. A comparison of animals containing the wild type or mutated integrin revealed that tumor cells expressing the mutated integrin resulted in a dramatic decrease in bone loss, unicortical or bicortical fractures and a decrease in the ability of tumor cells to reach the epiphyseal plate of the bone. Further, tumor cells within the bone expressing the integrin mutation prevented cancer induced spontaneous flinching, tactile allodynia, and movement evoked pain. Preventing A6 integrin cleavage on the prostate tumor cell surface decreased the migration of tumor cells within the bone and the onset and degree of bone pain and fractures. These results suggest that strategies for blocking the cleavage of the adhesion receptors on the tumor cell surface can significantly prevent cancer induced bone pain and slow disease progression within the bone. Since integrin cleavage is mediated by Urokinase-type Plasminogen Activator (uPA), further work is warranted to test the efficacy of uPA inhibitors for prevention or delay of cancer induced bone pain.     

The Pleistocene fauna (other than Primates) from Asbole, lower Awash Valley, Ethiopia, and its environmental and biochronological implications

The Asbole area in the Lower Awash Valley yielded a diverse fauna of large and small mammals, associated with an Acheulean industry. The most notable forms are a potentially new species of herpestid, a large collection of Kolpochoerus majus, and the earliest known Bos in Africa. Biochronologically, this fauna belongs to the earliest Middle Pleistocene, and is roughly contemporaneous with the Bodo site further south. Paleoenvironmentally, the fauna suggests a mosaic of landscapes among which humid environments, grasslands and forests, are predominant.     

Absence of post-translational aspartyl beta-hydroxylation of epidermal growth factor domains in mice leads to developmental defects and an increased incidence of intestinal neoplasia.

The BAH genomic locus encodes three distinct proteins: junctin, humbug, and BAH. All three proteins share common exons, but differ significantly based upon the use of alternative terminal exons. The biological roles of BAH and humbug and their functional relationship to junctin remain unclear. To evaluate the role of BAH in vivo, the catalytic domain of BAH was specifically targeted such that the coding regions of junctin and humbug remained undisturbed. BAH null mice lack measurable BAH protein in several tissues, lack aspartyl beta-hydroxylase activity in liver preparations, and exhibit no hydroxylation of the epidermal growth factor (EGF) domain of clotting Factor X. In addition to reduced fertility in females, BAH null mice display several developmental defects including syndactyly, facial dysmorphology, and a mild defect in hard palate formation. The developmental defects present in BAH null mice are similar to defects observed in knock-outs and hypomorphs of the Notch ligand Serrate-2. In this work, beta-hydroxylation of Asp residues in EGF domains is demonstrated for a soluble form of a Notch ligand, human Jagged-1. These results along with recent reports that another post-translational modification of EGF domains in Notch gene family members (glycosylation by Fringe) alters Notch pathway signaling, lends credence to the suggestion that aspartyl beta-hydroxylation may represent another post-translational modification of EGF domains that can modulate Notch pathway signaling. Previous work has demonstrated increased levels of BAH in certain tumor tissues and a role for BAH in tumorigenesis has been proposed. The role of hydroxylase in tumor formation was tested directly by crossing BAH KO mice with an intestinal tumor model, APCmin mice. Surprisingly, BAH null/APCmin mice show a statistically significant increase in both intestinal polyp size and number when compared with BAH wild-type/APCmin controls. These results suggest that, in contrast to expectations, loss of BAH catalytic activity may promote tumor formation.     

Identification of the components of a putative cytochrome bc1 complex in Rhodopseudomonas viridis

Chromatophore membranes isolated from the bacteriochlorophyll b-containing, photosynthetic purple nonsulfur bacterium, Rhodopseudomonas viridis, have been shown to contain a Rieske iron-sulfur protein, a cytochrome similar to cytochrome c1, and also at least one b-type cytochrome. These observations suggest the presence of a previously undetected cytochrome bc1 complex in this bacterium.