The selective forces acting on amino acid substitutions may be different in the two phases of molecular evolution: polymorphism and fixation. Negative selection and genetic drift may dominate the first phase, whereas positive selection may become much more significant in the second phase. However, the conventional dichotomy of synonymous vs. nonsynonymous changes does not offer the resolution needed to study the dynamics of these two phases. Following previously published methods, we separated amino acid changes into 75 elementary types (1-bp substitution between their respective codons). The likelihood of each type of amino acid change becoming polymorphic (PI, which stands for ''polymorphic index''), relative to synonymous changes, can then be calculated. Similarly, the likelihood of fixation (FI, for "fixation index"), conditional on common polymorphisms, is also calculated. Using Perlegen and HapMap data on human polymorphisms and the chimpanzee sequences as the outgroup, we compared the evolutionary dynamics of the 75 elementary changes in the two phases. We found a strong ''L-shaped'' negative correlation (P < 0.001) between FI and PI. Only those changes with low PIs show FI > 1, which is often a signature of adaptive evolution. These patterns suggest that negative and positive selection operate more effectively on the same set of amino acid changes and that Ϸ10 -13% of amino acid substitutions between humans and chimpanzee may be adaptive. 2). Many studies have attempted to address this issue by considering levels of within-species polymorphism or between-species divergence (3, 4). One may gain further resolution by dividing the process of mutation substitution into two separate phases, polymorphism and fixation. When a new mutation arises in a population, it exists as a low-frequency polymorphism. In this first phase of evolution, the dominant forces are genetic drift and negative selection. If this mutation can reach a substantial frequency (say, 20% in humans), then it is unlikely to be strongly deleterious. Hence, the second phase of evolution, the process of fixation, is governed mainly by drift and positive selection. Whether these two phases are positively or negatively correlated will inform us about how natural selection operates. In this report, we shall address these questions by using human data, but the approach should be general.To investigate the evolutionary dynamics and correlation between these two phases, we need to be able to classify mutations in coding regions into more categories than the traditional nonsynonymous and synonymous dichotomy. We follow the procedure developed by Tang et al. (refs. 5 and 6, see also ref. 7), who classified amino acid changes into 75 elementary types. An elementary amino acid change is one that can be reached by 1-bp substitution in the codons (Phe to Leu, for example). The rest of the 115 types are all composites of two or three elementary changes (Phe to Pro, for example). One can then ask how these 75 elementary changes differ in their likelihoods of ...

Mesoamerica has an important role in the expansion of Paleoamericans as the route to South America. In this study, we determined complete mitogenome sequences of 113 unrelated individuals from two indigenous populations of Mesoamerica, Mazahua and Zapotec. All newly sequenced mitogenomes could be classified into haplogroups A2, B2, C1 and D1, but one sequence in Mazahua was D4h3a, a subclade of haplogroup D4. This haplogroup has been mostly found in South America along the Pacific coast. Haplogroup X2a was not found in either population. Genetic similarity obtained using phylogenetic tree construction and principal component analysis showed that these two populations are distantly related to each other. Actually, the Mazahua and the Zapotec shared no sequences (haplotypes) in common, while each also showed a number of unique subclades. Surprisingly, Zapotec formed a cluster with indigenous populations living in an area from central Mesoamerica to Central America. By contrast, the Mazahua formed a group with indigenous populations living in external areas, including southwestern North America and South America. This intriguing genetic relationship suggests the presence of two paleo-Mesoamerican groups, invoking a scenario in which one group had expanded into South America and the other resided in Mesoamerica.

The Japanese wolf (Canis lupus hodophilax Temminck, 1839) was a subspecies of the gray wolf that inhabited the Japanese Archipelago and became extinct 100-120 years ago. In this study, we determined the whole genomes of nine Japanese wolves from the 19th- early 20th centuries and 11 Japanese dogs and analyzed them along with both modern and ancient wolves and dogs. Genomic analyses indicate that the Japanese wolf was a unique subspecies of the gray wolf that was genetically distinct from both modern and ancient gray wolves, lacking gene flow with other gray wolves. A Phylogenetic tree that minimizes the effects of introgression shows that Japanese wolves are closest to the dog monophyletic group among the gray wolves. Moreover, Japanese wolves show significant genetic affinities with East Eurasian dogs. We estimated the level of introgression from the ancestor of the Japanese wolves to the ancestor of East Eurasian dogs that had occurred in the transitional period from the Pleistocene to the Holocene, at an early stage after divergence from West Eurasian dog lineages. Because of this introgression, Japanese wolf ancestry has been inherited by many dogs through admixture between East Eurasian dog lineages. As a result of this heredity, up to 5.5% of modern dog genomes throughout East Eurasia are derived from Japanese wolf ancestry.