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...all effect, subject to inputs via mutation across many loci, maintenance by drift under sufficiently weak selection or small population size, and removal via purifying selection (Kryukov et al. 2007; =-=Bodmer and Bonilla 2008-=-); and (2) models based on the effects of rare, more highly-deleterious genetic or genomic variants, with common variants of small effect exerting a relatively-small influence on overall disease risk ...

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...ional-cognitive traits elaborated in the human lineage are selectively affected in this condition, which accords with studies positing and showing reduced function in autism of mirror neuron systems (=-=Hadjikhani et al. 2007-=-; Oberman and Ramachandran 2008) and Von Economo neurons (Allman et al. 2005), and altered asymmetry in brain regions subserving language (e. g., De Fossé et al. 2004; Knaus et al. 2008). From this pe...

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...ely-reduced social-brain functions, encompassing effects on social emotionality, social-causal thinking, empathy, and sense of self as well as language and reciprocal social interactions (Frith 2004; =-=Crespi and Badcock 2008-=-; Baron-Cohen 2009). Selective impairments in social cognition, with mechanistic language function and general intelligence largely unaffected, are specifically represented by the subset of autism spe...

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...chimpanzees (Herrmann et al. 2007), and (3) neurological studies of brain specializations of humans compared to other primates, most notably: (a) Von Economo neurons in the anterior cingulate cortex (=-=Allman et al. 2002-=-) that mediate aspects of complex social interaction (Allman et al. 2005) and selectively degenerate in frontotemporal dementia (Seeley et al. 2006), (b) left-right asymmetries in Broca’s area that un...

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...otic-affective cognition and behavior, especially creativity and relativelyenhanced verbal skills, reflect in part an ongoing history of human-specific selection and adaptation (Claridge et al. 1990; =-=Claridge 1997-=-; Nettle 2001; Barrantes-Vidal 2004; Nettle and Clegg 2006). This hypothesis is also supported by the extremely wide range of genetic and environmental factors that can convergently elicit psychosis (...

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...s of evil’. 4.1 NEURODEVELOPMENT, NEURODEGENERATION AND CANCER RISK A history of strong selection on brain size and functions, and concomitant evolution of increased lifespan, typify human evolution (=-=Allman et al. 1993-=-; Kaplan and Robson 2002), and humans are likewise unusual among mammals in their high incidence of cancer (Finch 2010) and broad suite of neurological andYear in Evolutionary Biology, in review, 201...

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...placenta (where imprinting effects are even more pervasive), plays a central role in the transfer of fitness-limiting resources between individuals that bear genes with partially-divergent interests (=-=Haig, 1993-=-, 1996, 1999, 2004a, 2007; Crespi & Badcock 2008; Davies et al. 2008; Bressan et al. 2009). Keverne (1996) conducted the first experiments to analyze imprinted gene effects in brain development, by cr...

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...eory, and additional evidence of genomic imprinting affecting hCG comes from a bioinformatic prediction of monoallelic expression of the lutenizing hormone/chorionic gonadotropin receptor gene LHCGR (=-=Allen et al. 2003-=-), suggesting the possible presence of reciprocal imprinting in fetal vs. maternal tissues for this ligand/receptor system, as demonstrated for the IGF2/IGF2R system in mice (Haig and Graham 1991). Su...

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...gy into the mainstream of the health sciences. A primary thesis of this review is that strong selection, in the contexts of geneticallybased intraspecific conflicts (Figure 1) (Burt and Trivers 2006; =-=Chapman 2006-=-; van Doorn 2009) and rapid evolution from other causes, has mediated a substantial proportion of human intrinsic disease risk. Strong selection impacts the evolution of disease risk in three main way...

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... positive selection, with some combination of male-female conflicts and sperm competition driving rapid evolutionary change that is adaptive in exclusively antagonistic contexts (Wyckoff et al. 2000; =-=Dorus et al. 2004-=-; Clark and Swanson 2005; Mank et al. 2008). Such antagonism should be exacerbated by enrichment to the X chromosome of not just brain and testis-expressed but also genes expressed in the prostate (Le...

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...all small body size (Monk and Moore 2004). The presence of a much more general pattern of imprinted gene dysregulation being associated with the development of obesity in humans (Gorlova et al. 2003; =-=Dong et al. 2005-=-; Guo et al. 2006; Haig 2008; Weinstein et al. 2009; Vrang et al. 2009) suggests that genomic conflict plays a central role in lipid metabolism in the fetal stage, in childhood, and in later life, wit...

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...ia risk genes show enhanced signals of positive selection along the human lineage,Year in Evolutionary Biology, in review, 2010, please do not circulate or cite 10 compared to sets of control genes (=-=Crespi et al. 2007-=-). These diverse findings link recent evolutionary changes in human cognition, neuroanatomy, gene expression, and allele and haplotype frequencies with alterations of these phenotypes in schizophrenia...

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...nd Campana 2000). The extreme diversity of placentalYear in Evolutionary Biology, in review, 2010, please do not circulate or cite 30 phenotypes among mammals, despite their shared, common function (=-=Crespi and Semeniuk 2004-=-; Elliot and Crespi 2006) attests to strong selection on the effects of gene expression in this organ, where effects of maternal-fetal conflicts, and genomic-imprinting conflicts, are known to be espe...

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...s well as the high genetic and clinical heterogeneity of autism (Abrahams and Geschwind 2009), suggest that studies of non-clinical populations using dimensional, social-cognitive perspectives (e. g. =-=Baron-Cohen et al. 2005-=-; Loat et al. 2008), are likely to uncover common genetic variants that mediate the expression of autistic traits more effectively than are genome-wide studies of autism per se (e. g., Weiss et al. 20...

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...ssues, such as the brain. SRY provides an example of this type of mechanism, in that it both initiates testicular development and mediates sex differentiation in the dopaminergic system of the brain (=-=Dewing et al. 2006-=-). Joint expression in brain and testis also appears to be pleiotropically linked with cancer risk due to effects on cell proliferation rates and DNA repair. For example, some of the well-known ‘micro...

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...mya (Sherwood et al. 2008; Vallender et al. 2008), and developed specializations for general intelligence, language, complex social cognition, social emotionality, and causal thinking more generally (=-=Alexander 1989-=-; Dunbar and Schulz 2007). Human reproduction has also evolved substantially, though less obviously: humans exhibit relatively-low per-copula fertility in association with concealed ovulation, anYear...

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...derlying signalling pathways and gene-expression patterns, are extensively deployed by cancer cells for the development and evolution of their broadly-similar cellular phenotypes (Figure 5) (see also =-=Bischof and Campana 2000-=-). The extreme diversity of placentalYear in Evolutionary Biology, in review, 2010, please do not circulate or cite 30 phenotypes among mammals, despite their shared, common function (Crespi and Seme...

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...l energetic and behavioral investment in offspring, setting up profound malefemale asymmetries in investment that have potentiated male-female conflicts over control of female reproductive resources (=-=Brown et al. 1997-=-; Chapman et al. 2003), genomic-imprinting conflicts in the placenta and brain (Renfree et al. 2009), and increased levels of competition between males and between sperm in the female reproductive tra...

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... from systems of reproductive ‘quality control’, whereby embryos are screened, as early as physiologically possible, for indicators of genetic and metabolic health and vigour (Haig 1993a, 1996, 2007; =-=Forbes 1997-=-, 2002). So-called ‘spontaneous’ early abortion of low-quality embryos imposes fitness costs on females, but a one-month delay in starting one’s next reproductive attempt represents a small cost compa...

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...er inter-birth intervals, menopause, and concomitant long female lifespan, with clear evidence of fitness benefits to children, from the local presence of grandmothers, reported for some populations (=-=Fox et al. 2009-=-). Life histories evolve as suites of changes in patterns of survivorship, reproduction, and parental care, with a central role for tradeoffs between aspects of growth, maintenance and reproduction. W...

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...t some facets of psychotic-affective cognition and behavior, especially creativity and relativelyenhanced verbal skills, reflect in part an ongoing history of human-specific selection and adaptation (=-=Claridge et al. 1990-=-; Claridge 1997; Nettle 2001; Barrantes-Vidal 2004; Nettle and Clegg 2006). This hypothesis is also supported by the extremely wide range of genetic and environmental factors that can convergently eli...

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...rowth. Evidence for a tradeoff between male fertility and cancer risk comes from studies the Y-linked TSPY1 gene, which exhibits positive correlations of gene copy number with human male sperm count (=-=Giachini et al. 2009-=-), and aberrant high expression of the gene associated with a range of cancers (Lau et al. 2009). More generally, mouse knock-outs of tumor-suppressor genes that are not lethal exhibit a striking prep...

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...ective implies that autism-spectrum conditions and psychoticaffective spectrum conditions represent genomically, neurodevelopmentally, and psychologically diametric diseases (Crespi and Badcock 2008; =-=Crespi et al. 2009-=-), due in part to diametric alterations, such as microdeletions vs microduplications, affecting genes involved in development of the human social brain (Crespi et al. 2009, 2010b). At least in princip...

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...ly-expressed imprinted genes, and involve overgrowth, increased incidence of autism, and other phenotypes that appear adapted to elicit increased maternal attention and resources (Oliver et al. 2007; =-=Eggermann et al. 2008-=-; Kent et al. 2008). In contrast to autism spectrum conditions, psychotic-affective spectrum conditions are mediated in part by genetic and epigenetic disruptions towards increased relative effects of...

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...ts from maternally-expressed imprinted genes (which tend to constrain growth), due to loss of imprinting and overexpression or maternal genes, or reduced paternal gene expression (McMinn et al. 2005; =-=Angiolini et al. 2006-=-). Such imprintedgene effects on fetal growth are largely a function of the central role of paternallyexpressed imprinted genes in driving placental growth and invasion (Kelsey 2007; Bressan et al. 20...

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... extension of the childhood stage, followed by a relatively-rapid transition to adulthood and an especially long adult stage, punctuated in females by a long post-reproductive period after menopause (=-=Bogin 2006-=-; Wells and Stock 2007). Evidence from inferred ages of fossil humans suggests that elongated lifespan in humans evolved quite recently, in the Upper Paleolithic (around 50,000 years ago) (Caspari and...

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...nmental changes, although both processes are intimately associated with human disease risk and both underscore the importance of considering disease risk in the context of maladaptation or trade-off (=-=Crespi 2000-=-; Nesse 2005) rather than pathology disembodied from recent evolutionary history. The primary forms of genomic conflict involved in the evolution of the human brain, reproduction, and life history are...

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...f factors, by the placenta, that damage maternal endothelial tissue. This proximate mechanism indicates a central role for maternalfetal conflicts in the evolution and etiology of pre-eclampsia risk (=-=Haig 1993-=-a), such that the effects of genetic and environmental risk factors depend critically upon evolved mechanisms of maternal and fetal manipulation and response (Haig 2004b; Yuan et al. 2005). To the ext...

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... et al. 2006). Atwal et al. (2009) report evidence of positive selection on MDM4, a key TP53-interacting gene, that they use to identify functional haplotypes that may influence cancer risk (see also =-=Ding et al. 2008-=-); comparisons of derived and ancestral haplotypes for such genes should also yield important insights into the genetic architectures of pleiotropy involving neurodevelopment and reproduction, in rece...

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...t analyses of how placental-uterine interactions constrain placental growth, during normal development of this organ, should yield novel insights into therapeutic agents for control of cancer (e. g., =-=Fest et al. 2008-=-). The prostate apparently represents a third arena for strong positive selection with increased cancer risk as a byproduct, although the normal functions of human prostate-specific gene expression ha...

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...either close or far from the disease threshold, but families with positive history are necessarily close and are expected to be segregating disease-risk alleles with moderate to large effects (e. g., =-=Arver et al. 2000-=-; BrandonYear in Evolutionary Biology, in review, 2010, please do not circulate or cite 23 et al. 2009). The degree to which segregating risk alleles of relatively small effect are relevant to diseas...

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...males may also be involved in the evolution of female fertilty levels, given that forms of hCG are produced at high levels in the male prostate and testis and transferred to females in seminal fluid (=-=Berger et al. 2007-=-), and that males should be under strong selection for the retention of embryos that they have sired. Genomic conflicts involving human chorionic gonadotropins generate a range of implications for hum...

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...hown enrichments of positive selection on polygenic disease genes, compared to other genes, in human populations (Nielsen et al. 2007; Blekhman et al. 2008; Lappalainen et al. 2009), and Amato et al. =-=(2009)-=- demonstrated higher levels of among-population differentiation, which can be indicative of divergent positive selection, in complex-disease genes than in a set of control genes. Several evolutionary-...

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...hown enrichments of positive selection on polygenic disease genes, compared to other genes, in human populations (Nielsen et al. 2007; Blekhman et al. 2008; Lappalainen et al. 2009), and Amato et al. =-=(2009)-=- demonstrated higher levels of among-population differentiation, which can be indicative of divergent positive selection, in complex-disease genes than in a set of control genes. Several evolutionary-...

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...lverman 2008), while neocortical functions subserve complex social interactions, including cooperation and altruism involving the mother and maternal kin. Badcock & Crespi (2006) and Crespi & Badcock =-=(2008)-=- describe genetic, physiological, neurological, psychological and behavioural evidence relevant to the hypothesis that the development of autism is strongly affected by imbalances in brain development...