Luca Cavalli-Sforza

The Role of Selection in the Evolution of Human Mitochondrial Genomes

High mutation rate in mammalian mitochondrial DNA generates a highly divergent pool of alleles even within species that have dispersed and expanded in size recently. Phylogenetic analysis of 277 human mitochondrial genomes revealed a significant (P < 0.01) excess of rRNA and nonsynonymous base substitutions among hotspots of recurrent mutation. Most hotspots involved transitions from guanine to adenine that, with thymine-to-cytosine transitions, illustrate the asymmetric bias in codon usage at synonymous sites on the heavy-strand DNA. The mitochondrion-encoded tRNAThr varied significantly more than any other tRNA gene. Threonine and valine codons were involved in 259 of the 414 amino acid replacements observed. The ratio of nonsynonymous changes from and to threonine and valine differed significantly (P = 0.003) between populations with neutral (22/58) and populations with significantly negative Tajimas D values (70/76), independent of their geographic location. In contrast to a recent suggestion that the excess of nonsilent mutations is characteristic of Arctic populations, implying their role in cold adaptation, we demonstrate that the surplus of nonsynonymous mutations is a general feature of the young branches of the phylogenetic tree, affecting also those that are found only in Africa. We introduce a new calibration method of the mutation rate of synonymous transitions to estimate the coalescent times of mtDNA haplogroups.

Y-Chromosome Evidence for a Northward Migration of Modern Humans into Eastern Asia during the Last Ice Age

The timing and nature of the arrival and the subsequent expansion of modern humans into eastern Asia remains controversial. Using Y-chromosome biallelic markers, we investigated the ancient human-migration patterns in eastern Asia. Our data indicate that southern populations in eastern Asia are much more polymorphic than northern populations, which have only a subset of the southern haplotypes. This pattern indicates that the first settlement of modern humans in eastern Asia occurred in mainland Southeast Asia during the last Ice Age, coinciding with the absence of human fossils in eastern Asia, 50,000-100,000 years ago. After the initial peopling, a great northward migration extended into northern China and Siberia.

Radiation of human mitochondria DNA types analyzed by restriction endonuclease cleavage patterns

SummaryHuman mitochondrial DNA (mtDNA) restriction endonuclease fragment patterns were analyzed using total blood cell DNA isolated from 200 individuals representing five different populations. Thirty-two fragment patterns (morphs) were observed with the enzymes Hpa I, Bam HI, Hae II, Msp I and Ava II yielding thirty-five different combinations of fragment patterns (mt DNA types). The major ethnic groups exhibit quantitative as well as qualitative differences in their mtDNA types, all of which are related to each other by a tree in which the closely related mtDNA types cluster according to geographic origin.Three mtDNA types are postulated to be ‘central’ to ethnic radiations due to their high frequencies, their appearance in more than one ethnic group, or their presence in other primate species. Genetic distances among populations were computed and employed in construction of an average linkage tree. If one of the three central mtDNA types is the root of the tree, differences in evolutionary rates among the branches become apparent. In particular, the Bushmen appear to have a higher evolutionary rate for mtDNA than the other four populations. Comparisons with nuclear gene frequencies suggest that this higher evolutionary rate may be the product of an elevated mutation rate or fixation of mutations in mtDNA.

Y chromosome haplotypes reveal prehistorical migrations to the Himalayas

By using 19 Y chromosome biallelic markers and 3 Y chromosome microsatellite markers, we analyzed the genetic structure of 31 indigenous Sino-Tibetan speaking populations (607 individuals) currently residing in East, Southeast, and South Asia. Our results showed that a T to C mutation at locus M122 is highly prevalent in almost all of the Sino-Tibetan populations, implying a strong genetic affinity among populations in the same language family. Furthermore, the extremely high frequency of H8, a haplotype derived from M122C, in the Sino-Tibetan speaking populations in the Himalayas including Tibet and northeast India indicated a strong bottleneck effect that occurred during a westward and then southward migration of the founding population of Tibeto-Burmans. We, therefore, postulate that the ancient people, who lived in the upper-middle Yellow River basin about 10,000 years ago and developed one of the earliest Neolithic cultures in East Asia, were the ancestors of modern Sino-Tibetan populations.

The great human expansion

Genetic and paleoanthropological evidence is in accord that today’s human population is the result of a great demic (demographic and geographic) expansion that began approximately 45,000 to 60,000 y ago in Africa and rapidly resulted in human occupation of almost all of the Earth’s habitable regions. Genomic data from contemporary humans suggest that this expansion was accompanied by a continuous loss of genetic diversity, a result of what is called the “serial founder effect.” In addition to genomic data, the serial founder effect model is now supported by the genetics of human parasites, morphology, and linguistics. This particular population history gave rise to the two defining features of genetic variation in humans: genomes from the substructured populations of Africa retain an exceptional number of unique variants, and there is a dramatic reduction in genetic diversity within populations living outside of Africa. These two patterns are relevant for medical genetic studies mapping genotypes to phenotypes and for inferring the power of natural selection in human history. It should be appreciated that the initial expansion and subsequent serial founder effect were determined by demographic and sociocultural factors associated with hunter-gatherer populations. How do we reconcile this major demic expansion with the population stability that followed for thousands years until the inventions of agriculture? We review advances in understanding the genetic diversity within Africa and the great human expansion out of Africa and offer hypotheses that can help to establish a more synthetic view of modern human evolution.

Darwinian selection and "altruism".

Models are proposed for evolution at a single locus affecting altruistic behavior in which genotypic fitnesses are Darwinian and frequency (but not density) dependent. The fitnesses are composed, either in a multiplicative or an additive way, of factors which depend on the receipt and donation of altruistic behavior. The factors are determined from the matrices of conditional probabilities which describe the genotypes of relatives. Since selection occurs, these probabilities are in terms of genotype frequencies. The relationship between the risk to helper and benefit to recipient which allows altruism to evolve is shown to depend on the kinship coefficient between helper and helped, the particular fitness function proposed and the degree of dominance of the altruism. The commonly accepted criteria of W. D. Hamilton [J. Theor. Biol. 7 (1964), 1–16, 17–52] apply only in the additive case. A second class of models of social cooperation independent of relationship and its evolutionary dynamics are discussed.

Analysis of evolution: Evolutionary rates, independence and treeness

Abstract Populations that separate according to a given pattern of fissions (a “tree” of descent) and evolve independently after fissions have a patterned variance—covariance matrix which reflects the history of fissions. Spectral analysis of the matrix can help reconstruct the pattern; multivariate analysis techniques can be used to test if an observed matrix is compatible with a given tree of descent, and with the assumption of constant or of variable evolutionary rates. We call these tests of “treeness” and discuss evolutionary implications, giving also an example on human evolution. The methods can be used more generally to test if a loss of information is involved in using a tree as a formal representation of any particular set of data.

Y chromosome diversity, human expansion, drift, and cultural evolution

The relative importance of the roles of adaptation and chance in determining genetic diversity and evolution has received attention in the last 50 years, but our understanding is still incomplete. All statements about the relative effects of evolutionary factors, especially drift, need confirmation by strong demographic observations, some of which are easier to obtain in a species like ours. Earlier quantitative studies on a variety of data have shown that the amount of genetic differentiation in living human populations indicates that the role of positive (or directional) selection is modest. We observe geographic peculiarities with some Y chromosome mutants, most probably due to a drift-related phenomenon called the surfing effect. We also compare the overall genetic diversity in Y chromosome DNA data with that of other chromosomes and their expectations under drift and natural selection, as well as the rate of fall of diversity within populations known as the serial founder effect during the recent “Out of Africa” expansion of modern humans to the whole world. All these observations are difficult to explain without accepting a major relative role for drift in the course of human expansions. The increasing role of human creativity and the fast diffusion of inventions seem to have favored cultural solutions for many of the problems encountered in the expansion. We suggest that cultural evolution has been subrogating biologic evolution in providing natural selection advantages and reducing our dependence on genetic mutations, especially in the last phase of transition from food collection to food production.

Y-chromosome diversity characterizes the Gulf of Oman

Arabia has served as a strategic crossroads for human disseminations, providing a natural connection between the distant populations of China and India in the east to the western civilizations along the Mediterranean. To explore this regions critical role in the migratory episodes leaving Africa to Eurasia and back, high-resolution Y-chromosome analysis of males from the United Arab Emirates (164), Qatar (72) and Yemen (62) was performed. The role of the Levant in the Neolithic dispersal of the E3b1-M35 sublineages is supported by the data, and the distribution and STR-based analyses of J1-M267 representatives points to their spread from the north, most likely during the Neolithic. With the exception of Yemen, southern Arabia, South Iran and South Pakistan display high diversity in their Y-haplogroup substructure possibly a result of gene flow along the coastal crescent-shaped corridor of the Gulf of Oman facilitating human dispersals. Elevated rates of consanguinity may have had an impact in Yemen and Qatar, which experience significant heterozygote deficiencies at various hypervariable autosomal STR loci.

An analysis of the genetics of schizophrenia

Abstract Data on the inheritance of schizophrenia indicate that both genetics and environment contribute importantly to the manifestation of the disease. However, heterogeneity of the data makes an accurate analysis very difficult. In this paper, a crude analysis of a threshold model, using a polygenic or a single gene hypothesis, shows that both are in approximate agreement with the data. Though argument about genetic models seems futile when virtually any model can account for the data, the single gene hypothesis is unavoidably more attractive at this stage. If a single gene is involved, the allele predisposing toward schizophrenia should be considered as essentially, though not entirely, recessive; all genotypes would be strongly affected by unknown environmental factors; and even some genetically normal individuals would manifest the disorder.