Evolutionary Selection Pressure Research Articles

The Potential Feasibility of Chlorinic Photosynthesis on Exoplanets

The modern search for life-bearing exoplanets emphasizes the potential detection of O(2) and O(3) absorption spectra in exoplanetary atmospheres as ideal signatures of biology. However, oxygenic photosynthesis may not arise ubiquitously in exoplanetary biospheres. Alternative evolutionary paths may yield planetary atmospheres tinted with the waste products of other dominant metabolisms, including potentially exotic biochemistries. This paper defines chlorinic photosynthesis (CPS) as biologically mediated photolytic oxidation of aqueous Cl(-) to form halocarbon or dihalogen products, coupled with CO(2) assimilation. This hypothetical metabolism appears to be feasible energetically, physically, and geochemically, and could potentially develop under conditions that approximate the terrestrial Archean. It is hypothesized that an exoplanetary biosphere in which chlorinic photosynthesis dominates primary production would tend to evolve a strongly oxidizing, halogen-enriched atmosphere over geologic time. It is recommended that astronomical observations of exoplanetary outgoing thermal emission spectra consider signs of halogenated chemical species as likely indicators of the presence of a chlorinic biosphere. Planets that favor the evolution of CPS would probably receive equivalent or greater surface UV flux than is produced by the Sun, which would promote stronger abiotic UV photolysis of aqueous halides than occurred during Earth's Archean era and impose stronger evolutionary selection pressures on endemic life to accommodate and utilize halogenated compounds. Ocean-bearing planets of stars with metallicities equivalent to, or greater than, the Sun should especially favor the evolution of chlorinic biospheres because of the higher relative seawater abundances of Cl, Br, and I such planets would tend to host. Directed searches for chlorinic biospheres should probably focus on G0-G2, F, and A spectral class stars that have bulk metallicities of +0.0 Dex or greater.

Pollination strategies in Cretan Arum lilies

Flowers of the genus Arum are known to attract dung-breeding flies and beetles through olfactory deceit. In addition to this strategy, the genus has evolved several other pollination mechanisms. The present study aimed to characterize the pollination strategies of the Cretan Arum species by investigating the flowering phenology, thermogeny, inflorescence odours, and the pollinating fauna. The results obtained show that Arum cyrenaicum and Arum concinnatum emit a strong dung smell and exhibit the distinctive features associated with this pollination syndrome. Both species are highly thermogenic, have a similar odour profile and attract small-bodied Diptera. Although sharing the same habitat, these two plant species are never found growing sympatrically as a result of the early blooming period of A. cyrenaicum. By contrast, Arum creticum and Arum idaeum have evolved a more traditional and mutually beneficial pollination mechanism. The stinking smell has been replaced by a more flower-like odour that attracts bees (Lasioglossum sp.) and, occasionally, bugs (Dionconotus cruentatus). Although attracting the same pollinator, the main compound present in the odour of A. creticum is different from that of A. idaeum. Principal component analysis (PCA), based on physiologically active components of the flower odours determined by testing on the antenna of the Lasioglossum bee, revealed two different clusters, indicating that pollinators can potentially discriminate between the odours of the two species. A further PCA on the main floral odour volatiles as identified by gas chroatography-mass spectroscopy from all the Arum species under investigation displayed odour-based similarities and differences among the species. The PCA-gas chomotographyelectroantennographic detection active peaks analysis showed that the two species, A. creticum and A. idaeum, form two groups and are clearly separated from A. cyrenaicum and A. concinnatum, which, conversely, cluster together. The evolutionary forces and selective pressures leading to diversification of pollination mechanisms in the Cretan Arum spp. are discussed. © 2010 The Linnean Society of London, Biological Journal of the Linnean Society, 2010, 101, 991–1001. ADDITIONAL KEYWORDS: Araceae – diversification – flower constancy – flowering time – odour – pollinator competition.

The last glacial-interglacial cycle in Lake Ohrid (Macedonia/Albania): testing diatom response to climate

Abstract. Lake Ohrid is a site of global importance for palaeoclimate research. This study presents results of diatom analysis of a ca. 136 ka sequence, Co1202, from the northeast of the lake basin. It offers the opportunity to test diatom response across two glacial-interglacial transitions and within the Last Glacial, while setting up taxonomic protocols for future research. The results are outstanding in demonstrating the sensitivity of diatoms to climate change, providing proxy evidence for temperature change marked by glacial-interglacial shifts between the dominant planktonic taxa, Cyclotella fottii and C. ocellata, and exact correlation with geochemical proxies to mark the start of the Last Interglacial at ca. 130 ka. Importantly, diatoms show much stronger evidence in this site for warming during MIS3 than recorded in other productivity-related proxies, peaking at ca. 39 ka, prior to the extreme conditions of the Last Glacial maximum. In the light of the observed patterns, and from the results of analysis of early Holocene sediments from a second core, Lz1120, the lack of a response to Late Glacial and early Holocene warming from ca. 14.7–6.9 ka suggests the Co1202 sequence may be compromised during this phase. After ca. 7.4 ka, there is evidence for enhanced nutrient enrichment compared to the Last Interglacial, followed by a post-Medieval loss of diversity which is consistent with cooling, but not definitive. Taxonomically, morphological variability in C. fottii shows no clear trends linked to climate, but an intriguing change in central area morphology occurs after ca. 48.7 ka, coincident with a tephra layer. In contrast, C. ocellata shows morphological variation in the number of ocelli between interglacials, suggesting climatically-forced variation or evolutionary selection pressure. The application of a simple dissolution index does not track preservation quality very effectively, underlining the importance of diatom accumulation data in future studies.

Vein patterning and evolution in C4plants

The C4photosynthetic pathway provides a platform to gain insight into the formation, regulation, and biological consequences of leaf vein pattern modification. This review examines the functional role of the vascular system in C4photosynthesis and the development of veins in C3and C4plants, highlighting the contribution of vasculature in the evolution of the C4pathway. With interest in developing C3plant crops into C4systems, it is essential to understand vascular patterning as a necessary element for C4functioning. Leaf venation in C4plants generally shows a higher vein density through a greater network complexity (more veins) compared with the ancestral C3condition. Thus, C4plants can provide a model that links the development of vein patterning with evolutionary selection pressures and molecular mechanisms (i.e., modifications of different components of vascular development). Numerous studies, including a comparative C3and C4Flaveria case study, highlight that the overall process of vein formation and patterning is complex, involving interactions between procambium and ground meristem during leaf ontogeny, and points to potential roles of changes in auxin production, transport, and perception.

Evolutionary ecology of mycorrhizal functional diversity in agricultural systems.

The root systems of most agronomic crops are colonized by diverse assemblages of arbuscular mycorrhizal fungi (AMF), varying in the functional benefits (e.g. nutrient transfer, pathogen protection, water uptake) provided to hosts. Little is known about the evolutionary processes that shape the composition of these fungal assemblages, nor is it known whether more diverse assemblages are beneficial to crop productivity. In this review we aim to identify the evolutionary selection pressures that shape AMF diversity in agricultural systems and explore whether promotion of AMF diversity can convincingly be linked to increases in agricultural productivity and/or sustainability. We then ask whether farmers can (and should) actively modify evolutionary selection pressures to increase AMF functioning. We focus on three agriculturally imposed selection regimes: tillage, fertilization, and continuous monoculture. We find that the uniform nature of these practices strongly selects for dominance of few AMF species. These species exhibit predictable, generally non-beneficial traits, namely heavy investment in reproduction at the expense of nutrient scavenging and transfer processes that are beneficial for hosts. A number of focus-points are given based on empirical and theoretical evidence that could be utilized to slow down negative selection pressures on AMF functioning, therein increasing crop benefit.

The origins of vertebrate adaptive immunity

Adaptive immunity is mediated through numerous genetic and cellular processes that generate favourable somatic variants of antigen-binding receptors under evolutionary selection pressure by pathogens and other factors. Advances in our understanding of immunity in mammals and other model organisms are revealing the underlying basis and complexity of this remarkable system. Although the evolution of adaptive immunity has been thought to occur by the acquisition of novel molecular capabilities, an increasing amount of information from new model systems suggest that co-option and redirection of pre-existing systems are the main source of innovation. We combine evidence from a wide range of organisms to obtain an integrated view of the origins and patterns of divergence in adaptive immunity.

Compound KIR‐HLA genotype analyses in the Iranian population by a novel PCR–SSP assay

Natural killer (NK) cells eliminate infected and transformed cells while still are self-tolerant. Interactions of the independently segregating Killer cell immunoglobulin-like receptors (KIR) and human leucocyte antigens (HLA) loci play a critical role in NK cell regulation. Different compound KIR-HLA genotypes can impart different thresholds of activation to the NK-cell repertoire and such genotypic variation has been found to confer altered risk in a number of human diseases including viral infections, autoimmune disorders, reproduction abnormalities and cancers. In this study, we presented a novel combined KIR-HLA polymerase chain reaction-sequence-specific primers genotyping assay for simultaneous determination of KIR genes and their three major HLA class I ligand groups (C1, C2, and Bw4). Moreover, known inhibitory and activating KIR + HLA (iKIR + HLA: 2DL2/3 + C1, 2DL1 + C2, 3DL1 + Bw4; and aKIR + HLA: 2DS2 + C1, 2DS1 + C2, 3DS1 + Bw4) combinations as well as co-inheritance of aKIR genes and iKIR + HLA pairs were analysed in a total of 200 unrelated healthy Iranian individuals. All tested subjects had at least one of the three iKIR + HLA pairs and the frequencies of various inhibitory combinations in the study group were: 31.5%, three iKIR + HLA pairs, 53.5%, two iKIR + HLA pairs, and 15%, 0ne iKIR + HLA pair. Furthermore, we revealed that majority of Iranians (69%) carry compound genotypes with greater number of inhibitory pairings than activating combinations (iKIR + HLA > aKIR + HLA). Conversely, iKIR + HLA < aKIR (45%) was dominant genotype in the study group. We conclude that selective evolutionary pressure has propensity to maintain KIR-HLA genotypes with more inhibitory combinations to guarantee self-tolerance. In contrast, existence of activating KIR genes without normal endogenous ligands, potentially arms the NK population for competent immunosurveillance and stronger defense against infections.

A comprehensive survey of human polymorphisms at conserved splice dinucleotides and its evolutionary relationship with alternative splicing.

BackgroundAlternative splicing (AS) is a key molecular process that endows biological functions with diversity and complexity. Generally, functional redundancy leads to the generation of new functions through relaxation of selective pressure in evolution, as exemplified by duplicated genes. It is also known that alternatively spliced exons (ASEs) are subject to relaxed selective pressure. Within consensus sequences at the splice junctions, the most conserved sites are dinucleotides at both ends of introns (splice dinucleotides). However, a small number of single nucleotide polymorphisms (SNPs) occur at splice dinucleotides. An intriguing question relating to the evolution of AS diversity is whether mutations at splice dinucleotides are maintained as polymorphisms and produce diversity in splice patterns within the human population. We therefore surveyed validated SNPs in the database dbSNP located at splice dinucleotides of all human genes that are defined by the H-Invitational Database.ResultsWe found 212 validated SNPs at splice dinucleotides (sdSNPs); these were confirmed to be consistent with the GT-AG rule at either allele. Moreover, 53 of them were observed to neighbor ASEs (AE dinucleotides). No significant differences were observed between sdSNPs at AE dinucleotides and those at constitutive exons (CE dinucleotides) in SNP properties including average heterozygosity, SNP density, ratio of predicted alleles consistent with the GT-AG rule, and scores of splice sites formed with the predicted allele. We also found that the proportion of non-conserved exons was higher for exons with sdSNPs than for other exons.ConclusionssdSNPs are found at CE dinucleotides in addition to those at AE dinucleotides, suggesting two possibilities. First, sdSNPs at CE dinucleotides may be robust against sdSNPs because of unknown mechanisms. Second, similar to sdSNPs at AE dinucleotides, those at CE dinucleotides cause differences in AS patterns because of the arbitrariness in the classification of exons into alternative and constitutive type that varies according to the dataset. Taking into account the absence of differences in sdSNP properties between those at AE and CE dinucleotides, the increased proportion of non-conserved exons found in exons flanked by sdSNPs suggests the hypothesis that sdSNPs are maintained at the splice dinucleotides of newly generated exons at which negative selection pressure is relaxed.

Long-term evolution of the Luteoviridae: time scale and mode of virus speciation.

Despite their importance as agents of emerging disease, the time scale and evolutionary processes that shape the appearance of new viral species are largely unknown. To address these issues, we analyzed intra- and interspecific evolutionary processes in the Luteoviridae family of plant RNA viruses. Using the coat protein gene of 12 members of the family, we determined their phylogenetic relationships, rates of nucleotide substitution, times to common ancestry, and patterns of speciation. An associated multigene analysis enabled us to infer the nature of selection pressures and the genomic distribution of recombination events. Although rates of evolutionary change and selection pressures varied among genes and species and were lower in some overlapping gene regions, all fell within the range of those seen in animal RNA viruses. Recombination breakpoints were commonly observed at gene boundaries but less so within genes. Our molecular clock analysis suggested that the origin of the currently circulating Luteoviridae species occurred within the last 4 millennia, with intraspecific genetic diversity arising within the last few hundred years. Speciation within the Luteoviridae may therefore be associated with the expansion of agricultural systems. Finally, our phylogenetic analysis suggested that viral speciation events tended to occur within the same plant host species and country of origin, as expected if speciation is largely sympatric, rather than allopatric, in nature.

The Subunit Interfaces of Weakly Associated Homodimeric Proteins

We analyzed subunit interfaces in 315 homodimers with an X-ray structure in the Protein Data Bank, validated by checking the literature for data that indicate that the proteins are dimeric in solution and that, in the case of the “weak” dimers, the homodimer is in equilibrium with the monomer. The interfaces of the 42 weak dimers, which are smaller by a factor of 2.4 on average than in the remainder of the set, are comparable in size with antibody–antigen or protease–inhibitor interfaces. Nevertheless, they are more hydrophobic than in the average transient protein–protein complex and similar in amino acid composition to the other homodimer interfaces. The mean numbers of interface hydrogen bonds and hydration water molecules per unit area are also similar in homodimers and transient complexes. Parameters related to the atomic packing suggest that many of the weak dimer interfaces are loosely packed, and we suggest that this contributes to their low stability. To evaluate the evolutionary selection pressure on interface residues, we calculated the Shannon entropy of homologous amino acid sequences at 60% sequence identity. In 93% of the homodimers, the interface residues are better conserved than the residues on the protein surface. The weak dimers display the same high degree of interface conservation as other homodimers, but their homologs may be heterodimers as well as homodimers. Their interfaces may be good models in terms of their size, composition, and evolutionary conservation for the labile subunit contacts that allow protein assemblies to share and exchange components, allosteric proteins to undergo quaternary structure transitions, and molecular machines to operate in the cell.

Genetic susceptibility in tuberculosis

The importance of host genetic factors in determining susceptibility to tuberculosis (TB) has been studied extensively using various methods, such as case-control, candidate gene and genome-wide linkage studies. Several important candidate genes like human leucocyte antigen/alleles and non-human leucocyte antigen genes, such as cytokines and their receptors, chemokines and their receptors, pattern recognition receptors (including toll-like receptors, mannose binding lectin and the dendritic cell-specific intercellular adhesion molecule-3 grabbing nonintegrin), solute carrier family 11A member 1 (formerly known as natural resistance-associated macrophage protein 1) and purinergic P2X7 receptor gene polymorphisms, have been associated with differential susceptibility to TB in various ethnic populations. This heterogeneity has been explained by host-pathogen and gene-environment interactions and evolutionary selection pressures. Although the achievements of genetics studies might not yet have advanced the prevention and treatment of TB, researchers have begun to widen their scope of investigation to encompass these practical considerations.

A comparative perspective on minicolumns and inhibitory GABAergic interneurons in the neocortex

Neocortical columns are functional and morphological units whose architecture may have been under selective evolutionary pressure in different mammalian lineages in response to encephalization and specializations of cognitive abilities. Inhibitory interneurons make a substantial contribution to the morphology and distribution of minicolumns within the cortex. In this context, we review differences in minicolumns and GABAergic interneurons among species and discuss possible implications for signaling among and within minicolumns. Furthermore, we discuss how abnormalities of both minicolumn disposition and inhibitory interneurons might be associated with neuropathological processes, such as Alzheimer's disease, autism, and schizophrenia. Specifically, we explore the possibility that phylogenetic variability in calcium-binding protein-expressing interneuron subtypes is directly related to differences in minicolumn morphology among species and might contribute to neuropathological susceptibility in humans.

Evolutionary Conservation of Phospholipid-Binding Sites in Membrane Proteins

Membrane proteins evolved to function in a diverse phospholipid environment. Experimental evidence suggests that some phospholipid molecules are recruited by membrane proteins as co-factors or ligands that tightly bind to specific sites on the protein surface and play important functional roles. In this work we have assessed the evolutionary conservation of phospholipid-binding sites in several alpha-helical and beta-barrel membrane proteins. We first identified the membrane protein surface residues and residues that are in close contact with co-crystallized phospholipids in the x-ray structures of adrenergic receptor, photosynthetic reaction center, Kcsa potassium channel, formate dehydrogenase and ferric hydroxamate uptake receptor using methods of computational geometry such as Delaunay triangulation and alpha shape. We next collected orthologous cDNA sequences for every protein and used posterior probability analysis of evolutionary selection pressure measured as ω-ratio with the aid of PAML package to identify phospholipid-facing residues under strong purifying selection pressure. We show that protein residues interacting with co-crystallized phospholipids are collectively more conserved than the rest of the phospholipid-facing residues with statistically significant p-values in the range 10e-7 - 10e-3. Additionally, we found that every phospolipid-binding site on the membrane protein surface contains from 3 to 5 residues that experience strong purifying selection pressure similar to the functionally important buried residues.

Positive selection of HIV host factors and the evolution of lentivirus genes.

BackgroundPositive selection of host proteins that interact with pathogens can indicate factors relevant for infection and potentially be a measure of pathogen driven evolution.ResultsOur analysis of 1439 primate genes and 175 lentivirus genomes points to specific host factors of high genetic variability that could account for differences in susceptibility to disease and indicate specific mechanisms of host defense and pathogen adaptation. We find that the largest amount of genetic change occurs in genes coding for cellular membrane proteins of the host as well as in the viral envelope genes suggesting cell entry and immune evasion as the primary evolutionary interface between host and pathogen. We additionally detect the innate immune response as a gene functional group harboring large differences among primates that could potentially account for the different levels of immune activation in the HIV/SIV primate infection. We find a significant correlation between the evolutionary rates of interacting host and viral proteins pointing to processes of the host-pathogen biology that are relatively conserved among species and to those undergoing accelerated genetic evolution.ConclusionsThese results indicate specific host factors and their functional groups experiencing pathogen driven evolutionary selection pressures. Individual host factors pointed to by our analysis might merit further study as potential targets of antiretroviral therapies.

Selective MyD88-dependent pathway inhibition by the cyanobacterial natural product malyngamide F acetate

In response to evolutionary selective pressure, prokaryotes have developed a rich array of secondary metabolites, some of which may be inhibitory to the innate immune system and the inflammatory response in vertebrates. We utilized the RAW264.7 macrophage cell line stimulated with LPS in a nitric oxide (NO) assay to screen for compounds with immunomodulatory activities from a library of marine natural products, and found that the malyngamide structure class, found commonly in the marine cyanobacterium Lyngbya majuscula, has potent activity. Several of the malyngamides were found to possess IC50 values of 5.4–18 µM. Malyngamide F acetate exhibited strong concentration-dependent anti-inflammatory activity in the NO assay with an IC50 of 7.1 µM and with no cytotoxicity at the concentrations tested. Subsequent real-time PCR of selected genes revealed a unique cytokine profile after LPS stimulation (TLR4) with decreased expression of iNOS, IL-1β, IL-6, and IL-10, but increased TNF-α expression. Additional experiments utilizing CpG and Poly I:C stimulation to selectively activate the MyD88-dependent and -independent pathways via TLR9 and TLR3 substantiated the finding that malyngamide F acetate selectively inhibits the MyD88-dependent pathway. To our knowledge, this is the first report of a natural product inhibiting the MyD88-dependent pathway.

Abstract IA-6: Single nucleotide polymorphisms in the p53 pathway

Abstract The p53 protein and the signal transduction pathway controlled by that protein responds to a wide variety of stress signals which can disrupt the fidelity of DNA replication and cell division. To prevent these errors or mutations the p53 pathway responds by initiating a process of cell cycle arrest, senescence or apoptosis which either permits repair of these errors or kills the clone of cells that contain these mutations. Central to this pathway are a series of proteins that respond to the stress signals and regulate the levels and activity of the p53 pathway. We have identified a number of single nucleotide polymorphisms (SNP) in those genes that regulate p53 activity and functions and these SNPs can play a role in the incidence of cancers in a population, the age of onset of cancers and the response to therapy. Some of the haplotypes containing these SNPs appear to be under positive evolutionary selection pressures in some human populations. The reason for this appears to be the role of p53 in the implantation of embryos into the uterus and the impact of some of these SNPs upon the fecundity of mice and humans. This process is mediated by the p53 regulated gene, Leukemia Inhibitory Factor or LIF, a cytokine that is essential for the implantation of embryos. SNPs in the p53 gene, the MDM-4 gene and the LIF gene regulate the efficiency of implantation of embryos in humans. It could well be that the p53 protein is also involved in the surveillance of developmental abnormalities. Citation Information: Cancer Res 2009;69(23 Suppl):IA-6.

Why Aire? Compensating for late bloomers.

The question under analysis in this commentary is, what was the evolutionary selection pressure that necessitated the ectopic expression of a subset of peripheral self-antigens in the thymus and by peripheral APC? The suggestion is that antigen expression is delayed until after the immune system is responsive.

Minireview: The SRC Family of Coactivators: An Entrée to Understanding a Subset of Polygenic Diseases?

In this perspective, we present the idea that SRC family coactivators are likely agents in human polygenic disease states based upon a number of interlocking aspects of their biology. We argue that their role as key integrators of environmental signals and their ability to regulate the expression of myriad downstream genes makes them likely candidates for strong positive evolutionary selection pressures. Based on the fact that they work as part of multiprotein coactivator complexes, we predict that individual coactivator alleles exist as weakly penetrant disease alleles, each contributing only a fraction of transcriptional activity to the whole coactivator complex. In this way, individual coactivator alleles are free to evolve in the absence of strong negative selection. Emerging genomic and proteomic approaches promise to advance the characterization of coactivator proteins and their physiological functions, allowing us to have a greater appreciation of their roles as master regulators at the nexus between genetics, reproduction, metabolism, cancer, other human diseases, and our environment.

Recent Natural Selection Identifies a Genetic Variant in a Regulatory Subunit of Protein Phosphatase 2A that Associates with Altered Cancer Risk and Survival

A regulated p53-dependent stress response is crucial in suppressing tumor formation and mediating the response to commonly used cancer therapeutics. However, little is known about the human, inherited genetics of this important signaling pathway. Studies of human genetic variants in the p53 tumor suppressor gene and MDM2 oncogene have shown that single nucleotide polymorphisms (SNP) can affect p53 signaling, confer cancer risk, and alter outcome, and also suggest that the pathway is under evolutionary selective pressure. Here, we attempt to accelerate the identification of functional p53 pathway SNPs by incorporating these characteristics into an analysis of 142 genes that are known to affect p53 signaling. We report that a genomic scan for recent natural selection denotes that of the 142 genes studied, the PPP2R5E gene that encodes a regulatory subunit of the tumor suppressing protein phosphatase 2A resides in a naturally selected genomic region. We go on to show that a selected SNP in PPP2R5E (epsilon-SNP2) associates with significant allelic differences in the onset (up to 19.2 years; P = 0.0002) and risk (odds ratio, up to 8.1; P = 0.0009) of soft tissue sarcoma development, as well as overall survival (relative risk, up to 3.04; P = 0.026). The PPP2R5E gene is identified as harboring genetic variants that can affect human cancer and are possibly under evolutionary selection pressure.

Altered tumor formation and evolutionary selection of genetic variants in the human MDM4 oncogene

A large body of evidence strongly suggests that the p53 tumor suppressor pathway is central in reducing cancer frequency in vertebrates. The protein product of the haploinsufficient mouse double minute 2 (MDM2) oncogene binds to and inhibits the p53 protein. Recent studies of human genetic variants in p53 and MDM2 have shown that single nucleotide polymorphisms (SNPs) can affect p53 signaling, confer cancer risk, and suggest that the pathway is under evolutionary selective pressure (1-4). In this report, we analyze the haplotype structure of MDM4, a structural homolog of MDM2, in several different human populations. Unusual patterns of linkage disequilibrium (LD) in the haplotype distribution of MDM4 indicate the presence of candidate SNPs that may also modify the efficacy of the p53 pathway. Association studies in 5 different patient populations reveal that these SNPs in MDM4 confer an increased risk for, or early onset of, human breast and ovarian cancers in Ashkenazi Jewish and European cohorts, respectively. This report not only implicates MDM4 as a key regulator of tumorigenesis in the human breast and ovary, but also exploits for the first time evolutionary driven linkage disequilibrium as a means to select SNPs of p53 pathway genes that might be clinically relevant.