Allelic variation in human mitochondrial genes based on patterns of restriction site polymorphism.

Whittam, Thomas S.; Clark, Andrew G.; Stoneking, Mark; Cann, Rebecca L.; Wilson, Allan C.

doi:10.1073/pnas.83.24.9611

Cited by 70 publications

(41 citation statements)

References 49 publications

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“…It is noteworthy that, in humans, ND3 exhibits the greatest diversity of restriction fragment length polymorphism haplotypes relative to neutral expectations of all mitochondrial loci (30). Mitochondrial genes may be potential targets of balancing selection because of the possibility of strong cytoplasmic-nuclear interactions (13).…”

Section: Resultsmentioning

confidence: 99%

Nonneutral evolution at the mitochondrial NADH dehydrogenase subunit 3 gene in mice.

Nachman

Boyer

Aquadro

1994

Proc. Natl. Acad. Sci. U.S.A.

139

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The neutral theory of molecular evolution asserts that while many mutations are deleterious and rapidly ellminated from populations, those that we observe as polymorphisms within populations are functionally equivalent to each other and thus neutral with respect to fitness. Mitochondrial DNA (mtDNA) is widely used as a genetic marker in evolutionary studies and is generally assumed to evolve according to a strictly neutral model of molecular evolution. One prediction of the neutral theory is that the ratio of replacement (nonsynonymous) to silent (synonymous) nucleotide substitutions will be the same within and between species. We To understand the genetic basis of evolutionary change, we must understand the extent to which selection governs the amount and distribution of genetic variation in natural populations. Considerable debate has centered on whether most naturally occurring genetic variants are strictly neutral (1), slightly deleterious (2), or advantageous (3). While these different views imply relatively small differences in selection coefficients, these differences can still have profound consequences for how molecular evolution occurs.The neutral theory, in its strictest form, asserts that while many mutations are strongly deleterious and therefore rapidly eliminated from populations, those that we observe within populations are equivalent with respect to fitness (1). The level of genetic variation within populations is determined by the neutral mutation rate and the effective population size. The amount of divergence between species is determined by the neutral mutation rate and the time since divergence. Under strict neutrality, the amount of variation within species is expected to be correlated with the rate of divergence between species for different genes or gene regions.A modification of the strictly neutral model, known as the nearly neutral or slightly deleterious model (2, 4), proposes that observed variants have a distribution of selective effects focused around neutrality. The extent to which these nearly neutral variants are affected by selection is a function of population size. Variants will behave as neutral if their effect on fitness is less than 1/2N in a diploid population of N individuals. Thus, in a large population, a larger fraction of nearly neutral mutations will be affected by selection. According to this model, the level of polymorphism within species and the rate ofdivergence between species depend on the population size.In addition to these two views, there are a variety ofmodels that describe how balancing selection can maintain variability within populations (e.g., ref. 5) and how directional selection can fix substitutions within populations (e.g., ref. 6).

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Section: Resultsmentioning

confidence: 99%

Nonneutral evolution at the mitochondrial NADH dehydrogenase subunit 3 gene in mice.

Nachman

Boyer

Aquadro

1994

Proc. Natl. Acad. Sci. U.S.A.

139

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“…1) and the approximately Poisson distribution of pairwise mtDNA differences in Caucasians and other non-African populations. The first two explanations assume that the differences among mtDNA variants are the result of neutral mutations (8)(9)(10). The third explanation invokes the action of positive selection on an advantageous mtDNA type.…”

Section: Discussionmentioning

confidence: 99%

“…We now show how the analysis of human mtDNA can give further insight into the evolutionary histories of populations. This advance has been made possible by the accumulation of sequences from the most variable part of mtDNA (4)(5)(6)(7), by analyses suggesting that most of the variation in mtDNA is selectively neutral (8)(9)(10), and by the consequent development of theoretical methods for estimating such parameters as the size and growth rate of a population (refs. 11 and 12; M. Slatkin and R. Hudson, personal communication).…”

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confidence: 99%

Branching pattern in the evolutionary tree for human mitochondrial DNA.

Rienzo

Wilson

1991

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

350

151

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Eighty-eight types of mitochondrial (mt) DNA were found by sequencing the most variable part of the control region from 117 Caucasians. In the tree relating those types, most of the branching events occur about two-thirds of the way from the root of the tree to the tips of the branches. Moreover, the distribution of sequence differences between all possible pairs of individuals is approximately Poisson. Other non-African populations show a similar pattern. Assuming a neutral model, these findings imply that the probability of survival of new lineages has undergone dramatic changes, probably due to population expansion. Conversely, African populations show multimodal distributions fitting with a model of constant population size.Owing to its fast evolution and maternal mode ofinheritance, mtDNA can provide knowledge of genetic relationships among closely related individuals (1, 2). This approach has been used to suggest that all present-day mtDNA variation in humans can be traced back to a common ancestor who probably lived in an African population (3)(4)(5). We now show how the analysis of human mtDNA can give further insight into the evolutionary histories of populations. This advance has been made possible by the accumulation of sequences from the most variable part of mtDNA (4-7), by analyses suggesting that most of the variation in mtDNA is selectively neutral (8-10), and by the consequent development of theoretical methods for estimating such parameters as the size and growth rate of a population (refs. 11 and 12; M. Slatkin and R. Hudson, personal communication).The present article applies one of these methods to the study of the demographic histories ofhuman populations. We present sequences for 117 individuals, mainly from Sardinia and the Middle East.t These sequences allow us to analyze the branching pattern in the genealogical tree and the distribution of pairwise sequence differences between individuals. The Sardinian and Middle Eastern patterns are then compared to those obtained from other populations (refs. 4, 5, and 10; R. Ward, B. Frazer, K. Dew, and S. Paabo, personal communication). Based on these patterns, theoretical expectations generated under the assumption of neutrality and different demographic conditions allow us to infer trends of population size through time for African and non-African populations.MATERIALS AND METHODS Population Samples. Sixty-nine placentas were collected in five maternity hospitals (Cagliari, Nuoro, Oristano, Ozieri, and Sassari) in Sardinia and the geographic origin of each sample was ascertained by the place of birth of the grandparents. The sampling strategy was designed to represent almost all linguistic areas except for one representing a recent foreign settlement (area 22). Sardinia was divided linguistically into 22 areas (14), which were grouped into five zones that are considered to be genetically homogeneous (15); zones A, B, C, D, and E include areas

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“…Later, Kimura (1983) proposed that deleterious mutations can contribute significantly to diversity but that at high frequencies they are selected against and prevented from becoming fixed. These predictions were examined in a number of studies using RFLP (Whittam et al 1986;Excoffier 1990;Merriwether et al 1991) or DNA sequence data (Tajima 1989), which indeed showed an excess in the number of rare variants than would be expected using Watterson's test (Watterson 1978) and/or Tajima's test (Tajima 1989).…”

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confidence: 99%