Paternal age and genetic load.

The incidence of base substitutions in humans increases with the age of the father, which shows up as an increased incidence of mutational disorders in the children of older fathers. There is a less obvious implication: an extended period of high average paternal age in a population will lead to increased genetic load. We mention some societies that have had high average paternal age for many generations. This may explain some surprising regional differences in recent measurements of deleterious mutations. High average paternal age also influences life history evolution, strengthening selection against mortality in late life while weakening selection against child mortality.

Group differences in proneness to inflammation.

All humans are primarily descendants from a diaspora out of Africa approximately 50,000 years ago although there are some indications of admixture with local populations of archaic humans outside Africa. The burden of infectious disease is greater in tropical Africa than elsewhere on earth in historic times, and it was less outside Africa, especially in the New World where passage through the Beringian filter kept many Old World parasites from entering the New World with humans. As a consequence we expect that the immune system, especially susceptibility to inflammation, will be "tuned up" in people with recent tropical African ancestry, intermediate in people of European and Asian ancestry, and perhaps "tuned down" in people of Native American ancestry. We suggest that evolved responses to different pathogen burdens among geographic groups may contribute to higher rates of inflammatory disease in modern people.

A genetic legacy from archaic Homo.

The roles of fossil human populations in the origin of modern humans have been enigmatic. Earlier (archaic) human populations were biologically similar and were in recurrent temporal and geographic contact, making interbreeding between ancient populations likely. Regardless of the taxonomic status of these populations, adaptive alleles may have introgressed from archaic populations into modern humans. When an introgressed archaic allele has a selective advantage, even rare interbreeding can lead to its spread or fixation in later human populations. Several genetic loci are candidates for such introgression, including microcephalin, a gene influencing brain development. This example may suggest that the evolution of human cognition depended in part on the genetic legacy of archaic groups such as the Neanderthals.

Recent acceleration of human adaptive evolution.

Genomic surveys in humans identify a large amount of recent positive selection. Using the 3.9-million HapMap SNP dataset, we found that selection has accelerated greatly during the last 40,000 years. We tested the null hypothesis that the observed age distribution of recent positively selected linkage blocks is consistent with a constant rate of adaptive substitution during human evolution. We show that a constant rate high enough to explain the number of recently selected variants would predict (i) site heterozygosity at least 10-fold lower than is observed in humans, (ii) a strong relationship of heterozygosity and local recombination rate, which is not observed in humans, (iii) an implausibly high number of adaptive substitutions between humans and chimpanzees, and (iv) nearly 100 times the observed number of high-frequency linkage disequilibrium blocks. Larger populations generate more new selected mutations, and we show the consistency of the observed data with the historical pattern of human population growth. We consider human demographic growth to be linked with past changes in human cultures and ecologies. Both processes have contributed to the extraordinarily rapid recent genetic evolution of our species.

Natural history of Ashkenazi intelligence.

This paper elaborates the hypothesis that the unique demography and sociology of Ashkenazim in medieval Europe selected for intelligence. Ashkenazi literacy, economic specialization, and closure to inward gene flow led to a social environment in which there was high fitness payoff to intelligence, specifically verbal and mathematical intelligence but not spatial ability. As with any regime of strong directional selection on a quantitative trait, genetic variants that were otherwise fitness reducing rose in frequency. In particular we propose that the well-known clusters of Ashkenazi genetic diseases, the sphingolipid cluster and the DNA repair cluster in particular, increase intelligence in heterozygotes. Other Ashkenazi disorders are known to increase intelligence. Although these disorders have been attributed to a bottleneck in Ashkenazi history and consequent genetic drift, there is no evidence of any bottleneck. Gene frequencies at a large number of autosomal loci show that if there was a bottleneck then subsequent gene flow from Europeans must have been very large, obliterating the effects of any bottleneck. The clustering of the disorders in only a few pathways and the presence at elevated frequency of more than one deleterious allele at many of them could not have been produced by drift. Instead these are signatures of strong and recent natural selection.

Genetic diversity and genetic burden in humans.

We discuss categories of genetic diversity in humans. Neutral diversity, population differences in frequencies of genetic markers that we think are invisible to natural selection, provides a passive record of population history but is otherwise of little interest in human biology. Genetic variation related to disease can be separated into mutational noise and variation due to selection, either ongoing selection else effects of a past environment. We distinguish consequences of genetic diversity for fitness, relevant to evolution, and consequences for well-being, relevant to medicine and public health. We call genetic variation that causes impairment of health or well-being of individual humans "apparent genetic burden" and variation that has effects on fitness but not well-being "unapparent genetic burden". We use "burden" to distinguish these notions from the classical concept of "genetic load" that refers to effects on population fitness, a concept formulated by Morton et al. [Morton, N.E., Crow, J.F., Muller, H.J., 1956. An estimate of the mutational damage in man from data on consanguineous marriages. Proc. Natl. Acad. Sci. U.S.A. 42, 855-863]. We distinguish adapted genes and adapted genotypes: an adapted gene is a gene that increases fitness of its bearer either in heterozygous or homozygous state or both, while an adapted genotype is a genotype that increases fitness of its bearer but is not transmitted intact to future generations. Balanced polymorphisms in which the heterozygote is superior in fitness may generate most adapted genotypes. In the face of major rapid environmental change adapted genotypes appear first but over time they are replaced by adapted genes. The presence of adapted genotypes is a good indication of recent environmental change: for example, there are apparently many polymorphisms in domestic animals of this nature, responses to domestication, and many fewer in wild animals (and in humans).

Expression of PKC-beta or cyclin D2 predicts for inferior survival in diffuse large B-cell lymphoma.

We sought to determine whether identification of poor-risk subgroups of diffuse large B-cell lymphoma (DLBCL) using immunohistochemical stains would have practical utility with regard to prognosis and therapeutic decisions. Tissue microarray blocks were created using replicate samples of formalin-fixed, paraffin-embedded tissue from 200 cases of de novo DLBCL. The sections were stained with antibodies to proteins that are expressed by activated or proliferating B cells including MUM1, FOXP1, bcl-2, survivin, protein kinase C-beta (PKC-beta), cyclin D2, cyclin D3, and Ki-67. In univariate analysis, tumor expression of cyclin D2 (P = 0.025) or PKC-beta (P = 0.015) was associated with a worse overall survival, whereas none of the other markers was predictive of overall survival. Patients with DLBCL that expressed either cyclin D2 or PKC-beta had a 5-year overall survival of only 30% as compared to 52% for those who were negative for both markers (P = 0.0019). In multivariate analysis, the expression of cyclin D2 or PKC-beta was an independent predictor of poor overall survival (P = 0.035). Cyclin D2 and PKC-beta expression will be useful in designing a 'biological prognostic index' for patients with DLBCL.

Resection of the inferior superior turbinate: does it affect olfactory ability or contain olfactory neuronal tissue?

BACKGROUND: One approach to the sphenoid sinus involves resection of the inferior portion of the superior turbinate. There is general agreement from anatomic investigations that this area contains olfactory mucosa. This study will determine if olfactory tissue can be found in the superior turbinate mucosa of patients with chronic sphenoiditis and what effect its removal has on a patient's olfactory ability. METHODS: The inferior one-third of the superior turbinate removed during endoscopic sphenoidotomy was stained with olfactory marker protein antibody, a marker for mature olfactory tissue. The specimens were graded for content of olfactory neuronal elements. All patients underwent uninasal 12-item smell identification testing before surgery and at least 3 weeks after surgery. RESULTS: Fifty-five superior turbinate samples were taken from 31 patients. Nine (16%) of 55 samples contained olfactory neuronal elements that stained with olfactory marker protein. When comparing the pre- and postoperative smell test results, 52% of the nostrils had no more than a one-item change, 35% of the nostrils had a more than one-item improvement, and only 12% had more than a one-item loss. None of the nostrils with a loss of olfactory ability after the surgery showed olfactory neuronal elements in their superior turbinate specimens. CONCLUSION: There is olfactory mucosa in approximately one-sixth of the superior turbinate specimens removed during the endoscopic transethmoidal sphenoidotomy procedure. Although 12% of the patients had a loss of olfactory ability in this study, none of the loss could be attributed to excision of olfactory tissue.

Genes, germs, and schizophrenia: an evolutionary perspective.

Literature on schizophrenia and other mental illnesses has emphasized the compatibility of evidence with genetic causation without adequately considering alternative hypotheses of disease causation. Although some studies from the mid-20th century reported associations between certain pathogens and schizophrenia, only recently has the possibility of infectious causation of schizophrenia again become an active focus of research. Infectious causation of schizophrenia is still, however, generally regarded as less well demonstrated than genetic causation. This article evaluates the evidence that has been used to support genetic and infectious causation. Our consideration of infectious causation focuses on the protozoan Toxoplasma gondii but also assesses other pathogens that may contribute to the development of some of the illnesses currently categorized as schizophrenia. Although evidence generally accepted as demonstrating genetic causation can be readily explained by hypotheses of infectious causation, some of the evidence implicating infectious causation cannot be similarly explained by genetic causation. This asymmetry indicates that a scientific approach to the causation of schizophrenia needs to put a greater emphasis on tests that distinguish hypotheses of genetic causation from those of infectious causation.