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We propose that conflict between paternally and maternally derived genes in the fetus explains three apparently unrelated observations in epidemiological studies of type 2 diabetes mellitus (DM2): (i) low birth weight is a risk factor for the development of DM2, (ii) there is a high prevalence of low birth weight among babies of fathers who develop DM2, and (iii) an exceptionally high prevalence of DM2 exists in modern day Arabs. Genetic conflict is caused by a particular relationship between the parents, their genes and their offspring: (i) mothers are sometimes polyandrous i.e. have children with more than one man, (ii) mothers provide more biological resources to the fetus than fathers, and (iii) the genes that regulate fetal growth come from both parents and both sets of genes determine the use of resources which are only those of the mother. There is a tendency for maternally derived genes (that promote fetal growth) to be suppressed, in order to spare use of mother's resources, while the same paternally derived genes tend to be expressed (to enhance use of the mother's resources). These same genes are pleiotropic: they affect not only fetal growth (birth weight) but also insulin resistance and hence the development of DM2. Polyandry increases differences in the expression between two parental alleles in the fetus i.e. increases genetic conflict and results in the production of bigger babies whereas monandry has the opposite effect. Consequently, parent-of-origin-biased expression of pleiotropic developmental genes could explain why smaller babies are more common when the fathers have DM2. Similarly less genetic conflict in Arabs (resulting from the tradition of strict monandry, the practice of levirate, and preference for a paternal cousin as spouse) could explain, at least in part, their exceptionally high prevalence of DM2. This hypothesis links human mate selection with the risk of developing DM2., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Westermarck's theory of incest taboo states that inhibition of sexual attraction between biologically close relatives is situational and develops during co-residence in early childhood. By contrast, the biological (genetic) basis of incest taboo is presumed from its universality in all human societies and animals and teleologically, from the need to prevent the detrimental effects of inbreeding. As incest taboo violation is infrequent, the frequency of the presumed gene in the population is believed to be near 100%. We present arguments which suggest that the incestuous gene may exist in all populations and could play an important role in evolution. When malaria emerged 10,000 years ago, human adaptation proceeded by the selection of protective genotypes. Among them, homozygotes for alpha-thalassemia, hemoglobin C, and Duffy antigen negative blood group, have better survival odds in malarious regions than heterozygotes and those with normal genotypes. Since consanguinity increases homozygosity, it increases the number of persons who are resistant to malaria. To pro-create, however, biologically close individuals must not feel sexual aversion that normally develops between those who spend their early childhood together (Westermarck effect). It is reasonable to assume, therefore, that mutation of the gene that discourages inbreeding may have appeared at an early time in evolution, and produced a weak Westermarck effect. This gene (we will call it anti-w) failed to inhibit mating between kins. Inbred offspring of anti-w carriers, would statistically, more likely carry both anti-w and homozygote genotypes which increase fitness in the presence of malaria. Today, alpha-thalassemia is the single most common monogenetic disorders in man with over 500 millions carriers concentrated in malarious regions of the world. The world's consanguineous population is some 500-800 millions and is also concentrated in malarious regions. Population migration has spread the gene outside areas of high malaria endemicity. However, endemicity of malaria provides a worldwide gradient of genotype frequencies which makes the incestuous gene hypothesis testable. We propose that the incestuous anti-w allele was co-selected with some of the genes protective against malaria because anti-w facilitates mating between genetically close individuals whose offspring better survive malaria.

Breast and ovarian cancer rates in Pakistan are significantly higher than in neighboring countries. The cancer rate discrepancies cannot be explained with discrepancies of their risk factors. We propose that observed cancer excess in Pakistan is due to cancer development by negative heterosis. Heterosis occurs when a hybrid has a phenotypic characteristic significantly different from that in either parent (hybrid vigor). At a molecular level, heterosis occurs in a heterozygote when one of the two alleles is inactivated. Gene inactivation occurs by methylation of cytosine in a promoter region of a gene. Initiation of allele inactivation is linked to the factors like stress, gender, diet, or another gene. In heterozygote, inactivation of one of the two tumor-suppressor alleles leads to monoallelic expression. This increases cancer risk in the same way the risk is increased in individual who inherit a single mutated tumor-suppressor gene (hereditary cancer syndrome). In both, cancer by heterosis and inherited cancer syndrome, cancer develops after inactivation of a second allele (second hit hypothesis). In a population, conditions that favor development of cancer by heterosis are those that favor mating of a large number of different homozygotes because they produce a large number of different heterozygotes. Among a large number of heterozygotes, there is an increased chance that some of hybrids will develop cancer by heterosis. In Pakistan, conditions were favorable for cancer development by heterosis because country has a high number of different ethnic groups and brotherhoods all of which have a higher rate of homozygosity due to a high frequency of consanguineous marriages, and marriages between members of different groups occurred because of intense population mixing. Result was birth of a large number of inter-ethnic/brotherhood hybrids (heterozygotes), some of which have developed cancer by heterosis.

Cervical carcinoma is caused by human papillomavirus (HPV). Among the risk factors for HPV infection are having multiple sex partners and sex partners who themselves had multiple sex partners. Women married to relatives are more likely to become infected with HPV and develop cervical carcinoma. Consanguineous spouses have a mild sexual aversion to each other that leads to sex avoidance and increases likelihood of satisfying sexual desire outside the marriage. Sexual aversion develops as a result of spouses growing together in early childhood, which triggers biological imprinting of Westermarck. Westermarck's effect prevents incest in nuclear family. In consanguineous family, it extends to spouses, producing mild sexual antipathy. Because of high prevalence of consanguinity worldwide, it is important to test this hypothesis.

We propose the hypothesis that around a main invading tumor, there are local metastases in the surrounding tissue/organ. They occur as a result of cancer cell migration through the interstitial matrix and we call them true local metastases. They are composed of individual or nested cells but are difficult to identify because of their nonspecific appearance, close location to the irregular surface of the main tumor and observer's inability to deduce a three dimensional structure from a few two-dimensional histological pictures. The propensity of neoplasms to locally metastasize may vary greatly among different types and stages of tumors. Better knowledge of a tumor's three dimensional spread may influence treatment strategy.