▪ Abstract Several unique properties of human mitochondrial DNA (mtDNA), including its high copy number, maternal inheritance, lack of recombination, and high mutation rate, have made it the molecule of choice for studies of human population history and evolution. Here we review the current state of knowledge concerning these properties, how mtDNA variation is studied, what we have learned, and what the future likely holds. We conclude that increasingly, mtDNA studies are (and should be) supplemented with analyses of the Y-chromosome and other nuclear DNA variation. Some serious issues need to be addressed concerning nuclear inserts, database quality, and the possible influence of selection on mtDNA variation. Nonetheless, mtDNA studies will continue to play an important role in such areas as examining socio-cultural influences on human genetic variation, ancient DNA, certain forensic DNA applications, and in tracing personal genetic history.

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Mitochondrial DNA and human evolution

The revolution that wasn't: a new interpretation of the origin of modern human behavior.

It is well known that a phylogenetic tree (gene tree) constructed from DNA sequences for a genetic locus does not necessarily agree with the tree that represents the actual evolutionary pathway of the species involved (species tree). One of the important factors that cause this difference is genetic polymorphism in the ancestral species. Under the assumption of neutral mutations, this problem can be studied by evaluating the probability (P) that a gene tree has the same topology as that of the species tree. When one gene (allele) is used from each of the species involved, the probability can be expressed as a simple function of Ti = ti/(2N), where ti is the evolutionary time measured in generations for the ith internodal branch of the species tree and N is the effective population size. When any of the Ti's is less than 1, the probability P becomes considerably less than 1.0. This probability cannot be substantially increased by increasing the number of alleles sampled from a locus. To increase the probability, one has to use DNA sequences from many different loci that have evolved independently of each other.

Relationships between gene trees and species trees.

To demonstrate a method for using genetic epidemiological data to assess the needs for equitable and cost-effective services for the treatment and prevention of haemoglobin disorders. We obtained data on demographics and prevalence of gene variants responsible for haemoglobin disorders from online databases, reference resources, and published articles. A global epidemiological database for haemoglobin disorders by country was established, including five practical service indicators to express the needs for care (indicator 1) and prevention (indicators 2-5). Haemoglobin disorders present a significant health problem in 71% of 229 countries, and these 71% of countries include 89% of all births worldwide. Over 330,000 affected infants are born annually (83% sickle cell disorders, 17% thalassaemias). Haemoglobin disorders account for about 3.4% of deaths in children less than 5 years of age. Globally, around 7% of pregnant women carry b or a zero thalassaemia, or haemoglobin S, C, D Punjab or E, and over 1% of couples are at risk. Carriers and at-risk couples should be informed of their risk and the options for reducing it. Screening for haemoglobin disorders should form part of basic health services in most countries.

/pdf/global-epidemiology-of-haemoglobin-disorders-and-derived-4rpyp3pdmo.pdf

Global epidemiology of haemoglobin disorders and derived service indicators

The proposal that all mitochondrial DNA (mtDNA) types in contemporary humans stem from a common ancestor present in an African population some 200,000 years ago has attracted much attention. To study this proposal further, two hypervariable segments of mtDNA were sequenced from 189 people of diverse geographic origin, including 121 native Africans. Geographic specificity was observed in that identical mtDNA types are shared within but not between populations. A tree relating these mtDNA sequences to one another and to a chimpanzee sequence has many deep branches leading exclusively to African mtDNAs. An African origin for human mtDNA is supported by two statistical tests. With the use of the chimpanzee and human sequences to calibrate the rate of mtDNA evolution, the age of the common human mtDNA ancestor is placed between 166,000 and 249,000 years. These results thus support and extend the African origin hypothesis of human mtDNA evolution.

https://science.sciencemag.org/content/sci/253/5027/1503.full.pdf

African populations and the evolution of human mitochondrial DNA

We describe a sensitive, reliable and reproducible method, based on three multiplex PCR assays, for the rapid detection of seven common alpha-thalassaemia deletions and one alpha-globin gene triplication. The new assay detects the alpha0 deletions - -SEA, - (alpha)20.5, - -MED, - -FIL and - -THAI in the first multiplex PCR, the second multiplex detects the -alpha3.7 deletion and alphaalphaalphaanti3.7 variant, the third multiplex detects the -alpha4.2 deletion. This simple multiplex method should greatly facilitate the genetic screening and molecular diagnosis of these determinants in populations where alpha-thalassaemias are prevalent.

https://onlinelibrary.wiley.com/doi/pdf/10.1046/j.1365-2141.2000.01870.x

Rapid detection of alpha-thalassaemia deletions and alpha-globin gene triplication by multiplex polymerase chain reactions.

Rapid detection and prenatal diagnosis of β-thalassaemia: studies in Indian and Cypriot populations in the UK

The beta-thalassaemia mutations in 702 unrelated carriers originating from seven different regions of the Indian subcontinent have been characterized using allele specific priming of the polymerase chain reaction (PCR). It was possible to identify the mutations in 688 (98%) of the individuals studied. Eleven different mutations were identified, of which five common ones accounted for 93.6%; namely the ones at IVS-1 position 5 (G-C), codons 8/9 (+G), IVS-1 position 1 (G-T), codons 41/42 (-CTTT) and the 619 bp deletion at the 3' end of the gene. The mutations at IVS-2 position 1 (G-A) and codon 30 (G-C), previously undescribed in Asian Indians, were found in two and six individuals respectively. Some regional variation in the distribution of beta-thalassaemia alleles was noted. These findings should prove useful for the development of a first trimester prenatal diagnosis programme based on direct detection of mutations.

The spectrum of beta-thalassaemia mutations on the Indian subcontinent: the basis for prenatal diagnosis.

First-trimester fetal diagnosis for haemoglobinopathies: three cases

The genetic relationships of human populations have been studied by comparing gene frequency data for protein and blood-group loci of different populations1,2. DNA analysis now promises to be more informative since not only do the DNA coding sequences have more variation than their corresponding proteins but, in addition, noncoding DNA sequences display more extensive polymorphism3,4. We have now studied the frequency of a group of closely linked nuclear DNA polymorphisms (haplotypes)5 in the β-globin gene cluster of normal (βA) chromosomes of individuals from eight diverse populations. We have found that all non-African populations share a limited number of common haplotypes whereas Africans have predominantly a different haplotype not found in other populations. Genetic distance analysis based on these nuclear DNA polymorphisms indicates a major division of human populations into an African and a Eurasian group.

John M. Old

Papers

Rapid detection of alpha-thalassaemia deletions and alpha-globin gene triplication by multiplex polymerase chain reactions.

Rapid detection and prenatal diagnosis of β-thalassaemia: studies in Indian and Cypriot populations in the UK

The spectrum of beta-thalassaemia mutations on the Indian subcontinent: the basis for prenatal diagnosis.

First-trimester fetal diagnosis for haemoglobinopathies: three cases

Evolutionary relationships of human populations from an analysis of nuclear DNA polymorphisms.