Selection against Heteroplasmy Explains the Evolution of Uniparental Inheritance of Mitochondria

Why are mitochondria almost always inherited from one parent during sexual reproduction? Current explanations for this evolutionary mystery include conflict avoidance between the nuclear and mitochondrial genomes, clearing of deleterious mutations, and optimization of mitochondrial-nuclear coadaptation. Mathematical models, however, fail to show that uniparental inheritance can replace biparental inheritance under any existing hypothesis. Recent empirical evidence indicates that mixing two different but normal mitochondrial haplotypes within a cell (heteroplasmy) can cause cell and organism dysfunction. Using a mathematical model, we test if selection against heteroplasmy can lead to the evolution of uniparental inheritance. When we assume selection against heteroplasmy and mutations are neither advantageous nor deleterious (neutral mutations), uniparental inheritance replaces biparental inheritance for all tested parameter values. When heteroplasmy involves mutations that are advantageous or deleterious (non-neutral mutations), uniparental inheritance can still replace biparental inheritance. We show that uniparental inheritance can evolve with or without pre-existing mating types. Finally, we show that selection against heteroplasmy can explain why some organisms deviate from strict uniparental inheritance. Thus, we suggest that selection against heteroplasmy explains the evolution of uniparental inheritance.     

Biparental Inheritance Through Uniparental Transmission: The Doubly Uniparental Inheritance (DUI) of Mitochondrial DNA

Many bivalvian mollusks have a sperm-transmitted mitochondrial genome (M), along with the standard egg-transmitted one (F). The phenomenon, known as doubly uniparental inheritance (DUI) of mtDNA, is the only known case in which biparental inheritance of a cytoplasmic genome is the rule rather than the exception. In the mussel Mytilus sperm mitochondria disperse randomly among blastomeres in female embryos, but form an aggregate and stay in the same blastomere in male embryos. In adults, somatic tissues of both sexes are dominated by the F genome. Sperm contains only the M genome and eggs the F (and perhaps traces of M). A female produces mostly daughters, mostly sons, or both sexes in about equal numbers, irrespective of its mate. Thus maleness and M mtDNA fate are tightly linked and under maternal control. Hybridization and triploidization affect the former but not the latter, which suggests that the two are not causally linked. Gene content and arrangement are the same in conspecific F and M genomes, but primary sequence has diverged from 20 % to 40 %, depending on species. The two genomes differ at the control region (CR). Synonymous substitutions accumulate faster in the M than the F genome and non-synonymous even faster. Expression studies indicate that the M genome is active only at spermatogenesis. These observations suggest that the M genome is under a more relaxed selective constraint than the F. Some mytilid species carry, in low frequencies, sperm-transmitted mtDNAs whose primary sequence is of the F type and the CR is an F/M mosaic (“masculinized” genomes). In venerids sperm mitochondria behavior, M genome fate and sex determination are as in mytilids. In unionids the M genome also evolves faster than the F and F/M sequence divergence reaches 50 %. The identification of F-specific and M-specific open reading frames in non-coding regions of unionids and mytilids, in conjunction with the CR’s mosaic structure of masculinized genomes, suggest that the mitochondrial genomes of species with DUI carry sequences that affect their transmission route. A model that incorporates these findings is presented in this review.     

Uniparental origin of sex chromosome polysomies.

The parental origin of the additional sex chromosomes in 8 cases with high-order sex chromosome polysomies was determined using DNA polymorphisms. The additional sex chromosomes were paternally derived in 3 48,XXYY cases, and maternal in origin in 1 48,XXXY case and 4 49,XXXXY cases. Thus, all extra chromosomes, within a particular patient, were always derived from only one parent. Their most likely origin was successive nondisjunction at the first and second meiotic division in one germ cell. The mechanism involved remains unclear, but appears to be independent of parental ages.     

池蝶蚌线粒体基因组双单性遗传现象分析

部分双壳贝类的线粒体遗传方式不同于标准的母系遗传(SMI),被称为双单性遗传现象(DUI)。池蝶蚌(Hyriopsis schlegelii)是淡水双壳贝类,是否存在双单性遗传现象?本文采用普通PCR扩增、SHOT-GUN测序及软件拼接获得了雄性池蝶蚌线粒体基因组(以下简称Hs-mtDNA)全序列,并与本实验室已报道的雌性池蝶蚌线粒体基因组全序列进行差异性分析。结果表明,雄性和雌性Hs-mtDNA全长分别为15961 bp和15939 bp,雄性比雌性长22 bp,雌雄线粒体基因组成与排列顺序一致。各蛋白编码基因的碱基数目均一致,碱基转换率为1.01%～7.34%,颠换率为0.00%～0.62%,氨基酸差异率为0.00%～9.35%;其中,COX1基因变异率为2.72%;COX2基因碱基变异率最高,达7.50%,雄性COX2的3'末端没有出现编码延伸区。雄性12S rRNA基因发生5 bp的碱基转换,差异率为0.6%;16S rRNA基因比雌性长9 bp,碱基差异率仅为1.2%。雌雄tRNA-His均位于H链上,介于COX2与ND3之间,没有出现位置的差异性。雌雄Hs-mtDNA的非编码区共有28个1～393 bp的片段,但未见控制区。在tRNA-Glu与tRNA-Tyr间有一段长393 bp的非编码区存在蛋白质翻译功能,但非雄性特异性蛋白。以COX1基因建立系统进化树,池蝶蚌和三角帆蚌(H.cumingii)聚在一起,而含有双单性遗传现象的无齿蚌属的Pyganodon grandis、小方蚌亚科的Venustaconcha ellipsiformis及小方形蚌属的Quadrula quadrula三者雄性聚为一支,雌性聚为一支。因此,雌雄池蝶蚌线粒体存在一定的差异性,但其差异要比其他具有双单性遗传现象的淡水双壳类小得多,且池蝶蚌线粒体遗传可能不存在双单性遗传现象。     

Statistical Analysis of Uniparental Disomy Data Using Hidden Markov Models

Genetic studies of uniparental disomy (UPD) employing many markers have helped geneticists to gain a better understanding of the molecular mechanisms underlying nondisjunction. However, most existing methods cannot simultaneously analyze all genetic markers and consistently incorporate crossover interference; they thus fail to make the most use of genetic information in the data. In the present article, we describe a hidden Markov model for multilocus uniparental disomy data. This method is based on the chi-square model for the crossover process and can simultaneously incorporate all marker information including untyped and uninformative markers. We then apply this novel method to analyze a set of UPD15 data.     

Uniparental Inheritance and Replacement of Mitochondrial DNA in Neurospora Tetrasperma

This study tested mechanisms proposed for maternal uniparental mitochondrial inheritance in Neurospora: (1) exclusion of conidial mitochondria by the specialized female reproductive structure, trichogyne, due to mating locus heterokaryon incompatibility and (2) mitochondrial input bias favoring the larger trichogyne over the smaller conidium. These mechanisms were tested by determining the modes of mitochondrial DNA (mtDNA) inheritance and transmission in the absence of mating locus heterokaryon incompatibility following crosses of uninucleate strains of Neurospora tetrasperma with trichogyne (trichogyne inoculated by conidia) and without trichogyne (hyphal fusion). Maternal uniparental mitochondrial inheritance was observed in 136 single ascospore progeny following both mating with and without trichogyne using mtDNA restriction fragment length polymorphisms to distinguish parental types. This suggests that maternal mitochondrial inheritance following hyphal fusions is due to some mechanism other than those that implicate the trichogyne. Following hyphal fusion, mututally exclusive nuclear migration permitted investigation of reciprocal interactions. Regardless of which strain accepted nuclei following seven replicate hyphal fusion matings, acceptor mtDNA was the only type detected in 34 hyphal plug and tip samples taken from the contact and acceptor zones. No intracellular mtDNA mixtures were detected. Surprisingly, 3 days following hyphal fusion, acceptor mtDNA replaced donor mtDNA throughout the entire colony. To our knowledge, this is the first report of complete mitochondrial replacement during mating in a filamentous fungus.     

Multimer Formation Explains Allelic Suppression of PRDM9 Recombination Hotspots

Genetic recombination during meiosis functions to increase genetic diversity, promotes elimination of deleterious alleles, and helps assure proper segregation of chromatids. Mammalian recombination events are concentrated at specialized sites, termed hotspots, whose locations are determined by PRDM9, a zinc finger DNA-binding histone methyltransferase. Prdm9 is highly polymorphic with most alleles activating their own set of hotspots. In populations exhibiting high frequencies of heterozygosity, questions remain about the influences different alleles have in heterozygous individuals where the two variant forms of PRDM9 typically do not activate equivalent populations of hotspots. We now find that, in addition to activating its own hotspots, the presence of one Prdm9 allele can modify the activity of hotspots activated by the other allele. PRDM9 function is also dosage sensitive; Prdm9^+/- heterozygous null mice have reduced numbers and less active hotspots and increased numbers of aberrant germ cells. In mice carrying two Prdm9 alleles, there is allelic competition; the stronger Prdm9 allele can partially or entirely suppress chromatin modification and recombination at hotspots of the weaker allele. In cell cultures, PRDM9 protein variants form functional heteromeric complexes which can bind hotspots sequences. When a heteromeric complex binds at a hotspot of one PRDM9 variant, the other PRDM9 variant, which would otherwise not bind, can still methylate hotspot nucleosomes. We propose that in heterozygous individuals the underlying molecular mechanism of allelic suppression results from formation of PRDM9 heteromers, where the DNA binding activity of one protein variant dominantly directs recombination initiation towards its own hotspots, effectively titrating down recombination by the other protein variant. In natural populations with many heterozygous individuals, allelic competition will influence the recombination landscape.     

Evaluation of the Role of Uniparental Disomy in Early Embryolethality of Man

We carried out systematic studies of the contribution of uniparental disomy for eight human chromosomes, 2, 9, 11, 15, 16, 19, 20, and 21, to the etiology of embryolethality. Most of these chromosomes have regions with orthologous imprinted genes syntenic with those on mouse chromosomes, the disturbed expression of which is related to embryolethality in mice. Screening of uniparental disomy in spontaneous abortuses of 5–16 weeks of pregnancy was performed by evaluation of the pattern of inheritance of alleles of polymorphic microsatellite loci located in the studied chromosomes. A total of 100 human embryos with cytogenetically determined normal karyotype were studied, in which arrest at the early stages of intrauterine development was determined by ultrasound examination of pregnant women. During this study, 13 embryos were discarded due to revealed karyotype anomalies or nonpaternity. No cases of uniparental disomy were found among the 87 studied abortuses for any of chromosomes studied. The analysis of the results of this study and four other studies concerning the search for uniparental disomy in dead embryos and fetuses did not reveal its elevated frequency in spontaneous abortuses as compared to the theoretically expected value based on evaluation of the probable combination of meiotic errors in human gametes. The data we obtained suggest that, first, uniparental disomies for human chromosomes that have regions with orthologous imprinted genes syntenic with mouse chromosomes do not contribute noticeably to the death of human embryos at the early developmental stages and, second, the mechanisms underlying embryolethality as a result of disturbed expression of imprinted loci differ markedly in evolutionarily remote mammals.     

Surgical Treatment of Intracranial Vascular Malformations

Arteriovenous malformations often pursue a progressive course, increasing in morbidity and mortality. Whenever possible they should be excised totally. The operating microscope, bipolar coagulation and high quality angiography have extended the generally accepted indications for surgical operation. Intraoperative adjuncts of contrast angiography and cardiac green have been helpful in accurately defining deep or complex lesions.     

N-3 Polyunsaturated Fatty Acids of Marine Origin and Multifocality in Human Breast Cancer

Objective

The microenvironment of breast epithelial tissue may contribute to the clinical expression of breast cancer. Breast epithelial tissue, whether healthy or tumoral, is directly in contact with fat cells, which in turn could influence tumor multifocality. In this pilot study we investigated whether the fatty acid composition of breast adipose tissue differed according to breast cancer focality.

Methods

Twenty-three consecutive women presenting with non-metastatic breast cancer underwent breast-imaging procedures including Magnetic Resonance Imaging prior to treatment. Breast adipose tissue specimens were collected during breast surgery. We established a biochemical profile of adipose tissue fatty acids by gas chromatography. We assessed whether there were differences according to breast cancer focality.

Results

We found that decreased levels in breast adipose tissue of docosahexaenoic and eicosapentaenoic acids, the two main polyunsaturated n-3 fatty acids of marine origin, were associated with multifocality.

Discussion

These differences in lipid content may contribute to mechanisms through which peritumoral adipose tissue fuels breast cancer multifocality.     

Uniparental Markers of Contemporary Italian Population Reveals Details on Its Pre-Roman Heritage

Background

According to archaeological records and historical documentation, Italy has been a melting point for populations of different geographical and ethnic matrices. Although Italy has been a favorite subject for numerous population genetic studies, genetic patterns have never been analyzed comprehensively, including uniparental and autosomal markers throughout the country.

Methods/Principal Findings

A total of 583 individuals were sampled from across the Italian Peninsula, from ten distant (if homogeneous by language) ethnic communities — and from two linguistic isolates (Ladins, Grecani Salentini). All samples were first typed for the mitochondrial DNA (mtDNA) control region and selected coding region SNPs (mtSNPs). This data was pooled for analysis with 3,778 mtDNA control-region profiles collected from the literature. Secondly, a set of Y-chromosome SNPs and STRs were also analyzed in 479 individuals together with a panel of autosomal ancestry informative markers (AIMs) from 441 samples. The resulting genetic record reveals clines of genetic frequencies laid according to the latitude slant along continental Italy – probably generated by demographical events dating back to the Neolithic. The Ladins showed distinctive, if more recent structure. The Neolithic contribution was estimated for the Y-chromosome as 14.5% and for mtDNA as 10.5%. Y-chromosome data showed larger differentiation between North, Center and South than mtDNA. AIMs detected a minor sub-Saharan component; this is however higher than for other European non-Mediterranean populations. The same signal of sub-Saharan heritage was also evident in uniparental markers.

Conclusions/Significance

Italy shows patterns of molecular variation mirroring other European countries, although some heterogeneity exists based on different analysis and molecular markers. From North to South, Italy shows clinal patterns that were most likely modulated during Neolithic times.