Genetics and recent human evolution

Starting with "mitochondrial Eve" in 1987, genetics has played an increasingly important role in studies of the last two million years of human evolution. It initially appeared that genetic data resolved the basic models of recent human evolution in favor of the "out-of-Africa replacement" hypothesis in which anatomically modern humans evolved in Africa about 150,000 years ago, started to spread throughout the world about 100,000 years ago, and subsequently drove to complete genetic extinction (replacement) all other human populations in Eurasia. Unfortunately, many of the genetic studies on recent human evolution have suffered from scientific flaws, including misrepresenting the models of recent human evolution, focusing upon hypothesis compatibility rather than hypothesis testing, committing the ecological fallacy, and failing to consider a broader array of alternative hypotheses. Once these flaws are corrected, there is actually little genetic support for the out-of-Africa replacement hypothesis. Indeed, when genetic data are used in a hypothesis-testing framework, the out-of-Africa replacement hypothesis is strongly rejected. The model of recent human evolution that emerges from a statistical hypothesis-testing framework does not correspond to any of the traditional models of human evolution, but it is compatible with fossil and archaeological data. These studies also reveal that any one gene or DNA region captures only a small part of human evolutionary history, so multilocus studies are essential. As more and more loci became available, genetics will undoubtedly offer additional insights and resolutions of human evolution.     

Origin and expansion of haplogroup H, the dominant human mitochondrial DNA lineage in West Eurasia: the Near Eastern and Caucasian perspective

More than a third of the European pool of human mitochondrial DNA (mtDNA) is fragmented into a number of subclades of haplogroup (hg) H, the most frequent hg throughout western Eurasia. Although there has been considerable recent progress in studying mitochondrial genome variation in Europe at the complete sequence resolution, little data of comparable resolution is so far available for regions like the Caucasus and the Near and Middle East-areas where most of European genetic lineages, including hg H, have likely emerged. This gap in our knowledge causes a serious hindrance for progress in understanding the demographic prehistory of Europe and western Eurasia in general. Here we describe the phylogeography of hg H in the populations of the Near East and the Caucasus. We have analyzed 545 samples of hg H at high resolution, including 15 novel complete mtDNA sequences. As in Europe, most of the present-day Near Eastern-Caucasus area variants of hg H started to expand after the last glacial maximum (LGM) and presumably before the Holocene. Yet importantly, several hg H subclades in Near East and Southern Caucasus region coalesce to the pre-LGM period. Furthermore, irrespective of their common origin, significant differences between the distribution of hg H sub-hgs in Europe and in the Near East and South Caucasus imply limited post-LGM maternal gene flow between these regions. In a contrast, the North Caucasus mitochondrial gene pool has received an influx of hg H variants, arriving from the Ponto-Caspian/East European area.     

African Haplogroup L mtDNA sequences show violations of clock-like evolution

A set of 96 complete mtDNA sequences that belong to the three major African haplogroups (L1, L2, and L3) was analyzed to determine if mtDNA has evolved as a molecular clock. Likelihood ratio tests (LRTs) were carried out with each of the haplogroups and with combined haplogroup sequence sets. Evolution has not been clock-like, neither for the coding region nor for the control region, in combined sets of African haplogroup L mtDNA sequences. In tests of individual haplogroups, L2 mtDNAs showed violations of a molecular clock under all conditions and in both the control and coding regions. In contrast, haplogroup L1 and L3 sequences, both for the coding and control regions, show clock-like evolution. In clock tests of individual L2 subclades, the L2a sequences showed a marked violation of clock-like evolution within the coding region. In addition, the L2a and L2c branch lengths of both the coding and control regions were shorter relative to those of the L2b and L2d sequences, a result that indicates lower levels of sequence divergence. Reduced median network analyses of the L2a sequences indicated the occurrence of marked homoplasy at multiple sites in the control region. After exclusion of the L2a and L2c sequences, African mtDNA coding region evolution has not significantly departed from a molecular clock, despite the results of neutrality tests that indicate the mitochondrial coding region has evolved under nonneutral conditions. In contrast, control region evolution is clock-like only at the haplogroup level, and it thus appears to have evolved essentially independently from the coding region. The results of the clock tests, the network analyses, and the branch length comparisons all caution against the use of simple mtDNA clocks.     

Slow mitochondrial DNA sequence evolution in the Anthozoa (Cnidaria)

Mitochondrial genes have been used extensively in population genetic and phylogeographical analyses, in part due to a high rate of nucleotide substitution in animal mitochondrial DNA (mtDNA). Nucleotide sequences of anthozoan mitochondrial genes, however, are virtually invariant among conspecifics, even at third codon positions of protein-coding sequences. Hence, mtDNA markers are of limited use for population-level studies in these organisms. Mitochondrial gene sequence divergence among anthozoan species is also low relative to that exhibited in other animals, although higher level relationships can be resolved with these markers. Substitution rates in anthozoan nuclear genes are much higher than in mitochondrial genes, whereas nuclear genes in other metazoans usually evolve more slowly than, or similar to, mitochondrial genes. Although several mechanisms accounting for a slow rate of sequence evolution have been proposed, there is not yet a definitive explanation for this observation. Slow evolution and unique characteristics may be common in primitive metazoans, suggesting that patterns of mtDNA evolution in these organisms differ from that in other animal systems.     

Ancient DNA analysis of human remains from the Upper Capital City of Kublai Khan

Analysis of DNA from human archaeological remains is a powerful tool for reconstructing ancient events in human history. To help understand the origin of the inhabitants of Kublai Khan's Upper Capital in Inner Mongolia, we analyzed mitochondrial DNA (mtDNA) polymorphisms in 21 ancient individuals buried in the Zhenzishan cemetery of the Upper Capital. MtDNA coding and noncoding region polymorphisms identified in the ancient individuals were characteristic of the Asian mtDNA haplogroups A, B, N9a, C, D, Z, M7b, and M. Phylogenetic analysis of the ancient mtDNA sequences, and comparison with extant reference populations, revealed that the maternal lineages of the population buried in the Zhenzishan cemetery are of Asian origin and typical of present-day Han Chinese, despite the presence of typical European morphological features in several of the skeletons.     

线粒体DNA突变与相关人类疾病

在过去的20年里, 人们发现线粒体DNA(mitochondrial DNA, mtDNA)突变与多种人类疾病相关, 其致病范围从单器官组织损害到多系统受累。文章目的在于探讨mtDNA突变与人类疾病的关系。文章重点论述: (1)线粒体遗传学特征; (2) mtDNA突变与人类遗传性疾病; (3)体细胞mtDNA突变在衰老和肿瘤中的作用; (4)mtDNA疾病的诊断和治疗。     

Phylogenetic network and physicochemical properties of nonsynonymous mutations in the protein-coding genes of human mitochondrial DNA

Theories on molecular evolution predict that phylogenetically recent nonsynonymous mutations should contain more non-neutral amino acid replacements than ancient mutations. We analyzed 840 complete coding-region human mitochondrial DNA (mtDNA) sequences for nonsynonymous mutations and evaluated the mutations in terms of the physicochemical properties of the amino acids involved. We identified 465 distinct missense and 6 nonsense mutations. 48% of the amino acid replacements changed polarity, 26% size, 8% charge, 32% aliphaticity, 13% aromaticity, and 44% hydropathy. The reduced-median networks of the amino acid changes revealed relatively few differences between the major continent-specific haplogroups, but a high variation and highly starlike phylogenies within the haplogroups. Some 56% of the mutations were private, and 25% were homoplasic. Nonconservative changes were more common than expected among the private mutations but less common among the homoplasic mutations. The asymptotic maximum of the number of nonsynonymous mutations in European mtDNA was estimated to be 1,081. The results suggested that amino acid replacements in the periphery of phylogenetic networks are more deleterious than those in the central parts, indicating that purifying selection prevents the fixation of some alleles.     

Absence of regional affinities of Neandertal DNA with living humans does not reject multiregional evolution

The recent extraction of mitochondrial DNA sequences from three European Neandertal fossils has led many to the conclusion that ancient DNA analysis supports the African replacement model of modern human origins and rejects models of multiregional evolution that propose some Neandertal ancestry in living humans. This conclusion is based, in part, on the lack of regional affinity of Neandertal DNA to that from living Europeans. Consideration of migration matrix models shows that this conclusion is premature, since under a model of interregional gene flow we expect to see similar levels of Neandertal ancestry in all contemporary regions, and living Europeans should not necessarily show closer affinity. The absence of regional affinity in Neandertal DNA does not distinguish between replacement and multiregional models.     

西藏牦牛线粒体DNA 的遗传多样性及系统进化分析

为从分子水平上探究西藏牦牛类群的遗传多样性、亲缘关系,本研究测定了日多牦牛、类乌齐牦牛、丁青牦牛、错那牦牛、隆子牦牛、仲巴牦牛、聂荣牦牛、申札牦牛等8 个西藏牦牛类群共328 头牦牛mtDNAD-loop区序列,分析其多态性,构建系统进化树。结果表明:本次测定的西藏牦牛mtDNA D-loop 区序列长度为 887 - 895 bp,共检测到135 个变异位点,其中单态突变位点52 个,简约信息位点83 个。在328 个个体中共检测出91 种单倍型,平均单倍型多样性(Hd)、平均核苷酸多样性(π)分别为0. 884、0.010 27,显示西藏牦牛具有丰富的遗传多样性。8 个类群间平均遗传距离为0.011;日多牦牛与错那牦牛间遗传距离最小(0. 006);类乌 齐牦牛与隆子牦牛间遗传距离最大(0.015)。系统进化分析显示西藏牦牛可分为两大类,错那牦牛是较纯的牦牛类群,其它牦牛类群在进化过程中出现相互交流的情况。     

The North African Middle Stone Age and its place in recent human evolution

The North African Middle Stone Age (NAMSA, ～300‐24 thousand years ago, or ka) features what may be the oldest fossils of our species as well as extremely early examples of technological regionalization and ‘symbolic’ material culture (d'Errico, Vanhaeren, Barton, Bouzouggar, Mienis, Richter, Hublin, McPherron, Louzouet, & Klein, 2009 ; Scerri, 2013a ; Richter, Grün, Joannes‐Boyau, Steele, Amani, Rué, Fernandes, Raynal, Geraads, Ben‐Ncer Hublin, McPherron, 2017 ). The geographic situation of North Africa and an increased understanding of the wet‐dry climatic pulses of the Sahara Desert also show that North Africa played a strategic role in continental‐scale evolutionary processes by modulating human dispersal and demographic structure (Drake, Blench, Armitage, Bristow, & White, 2011 ; Blome, Cohen, Tryon, Brooks, & Russell, 2012 ). However, current understanding of the NAMSA remains patchy and subject to a bewildering array of industrial nomenclatures that mask underlying variability. These issues are compounded by a geographic research bias skewed toward non‐desert regions. As a result, it has been difficult to test long‐established narratives of behavioral and evolutionary change in North Africa and to resolve debates on their wider significance. In order to evaluate existing data and identify future research directions, this paper provides a critical overview of the component elements of the NAMSA and shows that the timing of many key behaviors has close parallels with others in sub‐Saharan Africa and Southwest Asia.     

DNA重排及体外分子进化

ＤＮＡ重排是目前为止最简便、最有效的体外定向进化技术,可以对单一基因、质粒、代谢途径、部分甚至整个基因组进行改造。本综述了ＤＮＡ重排的基本原理、特点、与其它体外进化技术的不同,着重介绍了其在体外分子进化上的广泛应用,并对应用前景进行了展望。     

The majority of recent short DNA insertions in the human genome are tandem duplications

Nucleotide substitutions, insertions, and deletions constitute the principal molecular mechanisms generating genetic variation on small length scales. In contrast to substitutions, the nature of short DNA insertions and deletions (indels) is far less understood. With the recent availability of whole-genome multiple alignments between human and other primates, detailed investigations on indel characteristics and origin have come within reach. Here, we show that the majority of short (1-100 bp) DNA insertions in the human lineage are tandem duplications of directly adjacent sequence segments with conserved polarity. Indels in microsatellites comprise only a small fraction. The underlying molecular processes generating indels do not necessarily rely on the presence of preexisting duplicates, as would be expected for unequal crossing over, as well as replication slippage. Instead, our findings point toward a mechanism that preferentially occurs in the male germline and is not recombination-mediated. Surprisingly, nonframeshifting tandem duplications and deletions in coding regions still occur at approximately 50% of their genomic background rates. As is already well established in the context of gene and segmental duplications, our results demonstrate that duplications are also likely to constitute the predominant process for rapid generation of new genetic material and function on smaller scales.     

Defects in mitochondrial DNA replication and human disease

Mitochondrial DNA (mtDNA) is replicated by the DNA polymerase g in concert with accessory proteins such as the mtDNA helicase, single stranded DNA binding protein, topoisomerase, and initiating factors. Nucleotide precursors for mtDNA replication arise from the mitochondrial salvage pathway originating from transport of nucleosides, or alternatively from cytoplasmic reduction of ribonucleotides. Defects in mtDNA replication or nucleotide metabolism can cause mitochondrial genetic diseases due to mtDNA deletions, point mutations, or depletion which ultimately cause loss of oxidative phosphorylation. These genetic diseases include mtDNA depletion syndromes such as Alpers or early infantile hepatocerebral syndromes, and mtDNA deletion disorders, such as progressive external ophthalmoplegia (PEO), ataxia-neuropathy, or mitochondrial neurogastrointestinal encephalomyopathy (MNGIE). This review focuses on our current knowledge of genetic defects of mtDNA replication (POLG, POLG2, C10orf2) and nucleotide metabolism (TYMP, TK2, DGOUK, and RRM2B) that cause instability of mtDNA and mitochondrial disease.     

Morphological evolution and genetic differentiation in Daphnia species complexes

Despite many ecological and evolutionary studies, the history of several species complexes within the freshwater crustacean genus Daphnia (Branchiopoda, Anomopoda) is poorly understood. In particular, the Daphnia longispina group, comprising several large-lake species, is characterized by pronounced phenotypic plasticity, many hybridizing species and backcrossing. We studied clonal assemblages from lakes and ponds comprising daphnids from several species complexes. In order to reveal patterns of reticulate evolution and introgression among species, we analysed three data sets and compared nuclear, mtDNA and morphological divergence using animals from 158 newly established clonal cultures. By examining 15 nuclear and 11 mitochondrial (12S/16S rDNA) genetic characters (allozymes/restriction enzymes), and 48 morphological traits, we found high clonal diversity and discontinuities in genotypic and morphological space which allowed us to group clones by cytonuclear differentiation into seven units (outgroup D. pulex). In contrast to six groups emerging from nuclear divergence (related to three traditional species, D. cucullata, D. galeata, D. hyalina and three pairwise intermediate hybrids), a seventh group of clones was clearly resolved by morphological divergence: distinct mtDNA haplotypes within one nuclear defined cluster, ‘D. hyalina’, resembled traditional D. hyalina and D. rosea phenotypes, respectively. In other nuclear defined clusters, association between mtDNA haplotype and morphology was low, despite hybridization being bidirectional (reciprocal crosses). Morphological divergence was greatest between young sister species which are separated on the lake/pond level, suggesting a significant role for divergent selection during speciation along with habitat shifts. Phylogenetic analyses were restricted to four cytonuclear groups of clones related to species. mtDNA and nuclear phylogenies were consistent in low genetic divergence and monophyly of D. hyalina and D. rosea. Incongruent patterns of phylogenies and different levels of genetic differentiation between traditional species suggest reticulate evolutionary processes.     

Cold spots of human mitochondrial DNA hypervariable segment 1

The distribution of mutations in hypervariable segment 1 (HVS1) of mitochondrial DNA (mtDNA) was analyzed for more than 37000 individuals from various regions of the world. The results were used to estimate the intensity of mutation processes and the features of the cold spot distribution in mtDNA. Analysis of the structural-functional organization and variation of HVS1 made it possible to associate a lower variation with functionally important HVS1 regions. The distribution of CAT cold spots in secondary DNA structures revealed a lack of correlation between the cold spot location and the structural type of the mtDNA region.     

Nanopore sequencing identifies a higher frequency and expanded spectrum of mitochondrial DNA deletion mutations in human aging

Mitochondrial DNA (mtDNA) deletion mutations cause many human diseases and are linked to age-induced mitochondrial dysfunction. Mapping the mutation spectrum and quantifying mtDNA deletion mutation frequency is challenging with next-generation sequencing methods. We hypothesized that long-read sequencing of human mtDNA across the lifespan would detect a broader spectrum of mtDNA rearrangements and provide a more accurate measurement of their frequency. We employed nanopore Cas9-targeted sequencing (nCATS) to map and quantitate mtDNA deletion mutations and develop analyses that are fit-for-purpose. We analyzed total DNA from vastus lateralis muscle in 15 males ranging from 20 to 81 years of age and substantia nigra from three 20-year-old and three 79-year-old men. We found that mtDNA deletion mutations detected by nCATS increased exponentially with age and mapped to a wider region of the mitochondrial genome than previously reported. Using simulated data, we observed that large deletions are often reported as chimeric alignments. To address this, we developed two algorithms for deletion identification which yield consistent deletion mapping and identify both previously reported and novel mtDNA deletion breakpoints. The identified mtDNA deletion frequency measured by nCATS correlates strongly with chronological age and predicts the deletion frequency as measured by digital PCR approaches. In substantia nigra, we observed a similar frequency of age-related mtDNA deletions to those observed in muscle samples, but noted a distinct spectrum of deletion breakpoints. NCATS-mtDNA sequencing allows the identification of mtDNA deletions on a single-molecule level, characterizing the strong relationship between mtDNA deletion frequency and chronological aging.     

Genetic structuring and recent demographic history of red pandas (Ailurus fulgens) inferred from microsatellite and mitochondrial DNA

Clarification of the genetic structure and population history of a species can shed light on the impacts of landscapes, historical climate change and contemporary human activities and thus enables evidence‐based conservation decisions for endangered organisms. The red panda (Ailurus fulgens) is an endangered species distributing at the edge of the Qinghai‐Tibetan Plateau and is currently subject to habitat loss, fragmentation and population decline, thus representing a good model to test the influences of the above‐mentioned factors on a plateau edge species. We combined nine microsatellite loci and 551 bp of mitochondrial control region (mtDNA CR) to explore the genetic structure and demographic history of this species. A total of 123 individuals were sampled from 23 locations across five populations. High levels of genetic variation were identified for both mtDNA and microsatellites. Phylogeographic analyses indicated little geographic structure, suggesting historically wide gene flow. However, microsatellite‐based Bayesian clustering clearly identified three groups (Qionglai‐Liangshan, Xiaoxiangling and Gaoligong‐Tibet). A significant isolation‐by‐distance pattern was detected only after removing Xiaoxiangling. For mtDNA data, there was no statistical support for a historical population expansion or contraction for the whole sample or any population except Xiaoxiangling where a signal of contraction was detected. However, Bayesian simulations of population history using microsatellite data did pinpoint population declines for Qionglai, Xiaoxiangling and Gaoligong, demonstrating significant influences of human activity on demography. The unique history of the Xiaoxiangling population plays a critical role in shaping the genetic structure of this species, and large‐scale habitat loss and fragmentation is hampering gene flow among populations. The implications of our findings for the biogeography of the Qinghai‐Tibetan Plateau, subspecies classification and conservation of red pandas are discussed.     

Lack of mitochondrial DNA divergence between chromosome races of the common shrew, Sorex araneus, in Sweden. Implications for interpreting chromosomal evolution and colonization history

The common shrew, Sorex araneus, has one of the most variable karyotypes among mammals, displaying numerous chromosome races throughout its distribution. The six chromosome races present in Sweden can be categorized in two different karyotypic groups, the west and north European karyotypic groups (western and northern). Three races belonging to the western group are considered to have arisen through whole arm reciprocal translocations (WARTs). Race formation through this process requires a bottleneck event. In the present study we sequenced a part of the mitochondrial DNA (mtDNA) genome to investigate molecular differences between the chromosome races in Sweden. We found no mtDNA differentiation between the mainland chromosome races or the karyotypic groups. Genetic variation is as large between populations within a race as between populations among the races or karyotypic groups, suggesting that the karyotypic groups might have originated in a common glacial refugium. The noticeable exception is the Oland race, which shows higher mtDNA diversity compared to the other Swedish races, indicating a divergent origin difficult to explain. Mitochondrial DNA variation in Sweden suggests that most haplotypes arose in situ and that the populations has undergone a rapid size expansion. Altogether, the mtDNA data are in agreement with the WART hypothesis, which still holds as the most plausible variant of karyotype evolution for three of the chromosome races of the common shrew in Sweden.