An unbiased resource of novel SNP markers provides a new chronology for the human Y chromosome and reveals a deep phylogenetic structure in Africa.

Sequence diversity and the ages of the deepest nodes of the MSY phylogeny remain largely unexplored due to the severely biased collection of SNPs available for study. We characterized 68 worldwide Y chromosomes by high-coverage next-generation sequencing, including 18 deep-rooting ones, and identified 2386 SNPs, 80% of which were novel. Many aspects of this pool of variants resembled the pattern observed among genome-wide de novo events, suggesting that in the MSY, a large proportion of newly arisen alleles has survived in the phylogeny. Some degree of purifying selection emerged in the form of an excess of private missense variants. Our tree recapitulated the previously known topology, but the relative lengths of major branches were drastically modified and the associated node ages were remarkably older. We found significantly different branch lengths when comparing the rare deep-rooted A1b African lineage with the rest of the tree. Our dating results and phylogeography led to the following main conclusions: (1) Patrilineal lineages with ages approaching those of early AMH fossils survive today only in central-western Africa; (2) only a few evolutionarily successful MSY lineages survived between 160 and 115 kya; and (3) an early exit out of Africa (before 70 kya), which fits recent western Asian archaeological evidence, should be considered. Our experimental design produced an unbiased resource of new MSY markers informative for the initial formation of the anatomically modern human gene pool, i.e., a period of our evolution that had been previously considered to be poorly accessible with paternally inherited markers.

Parkinson's disease: a complex interplay of mitochondrial DNA alterations and oxidative stress.

Parkinson's disease (PD) is one of the most common age-related neurodegenerative diseases. This pathology causes a significant loss of dopaminergic neurons in the Substantia Nigra. Several reports have claimed a role of defective nuclear and mitochondrial DNA repair pathways in PD etiology, in particular, of the Base Excision Repair (BER) system. In addition, recent findings, related to PD progression, indicate that oxidative stress pathways involving c-Abl and GST could also be implicated in this pathology. This review focuses on recently described networks most likely involved in an integrated manner in the course of PD.

The landscape of Y chromosome polymorphisms in Russia.

BACKGROUND: The pattern of diversity for the Y chromosome provides a view of male-driven processes of dispersal and settlement. By virtue of the broad geographic continuity, the genetic signature of movements from Asia to Europe can be detected in populations of north-eastern Europe. AIM: To directly test previous hypotheses on the peopling of Russia, by considering a broader spectrum of potential diversity. SUBJECTS AND METHODS: A total of 636 unrelated males (24 samples) from geographically and ethnically defined populations of Russia, Belarus, Azerbaijan and Georgia were analysed for 16 Y-STR loci. Some of the populations represent more or less distinct isolates. RESULTS: Microsatellites alone can have the power of detecting Asian contributions to the gene pool of populations now residing in Europe. Within Europe, a greater heterogeneity among populations sharing the same language than between populations sharing the same ethnic affiliation was found. There was low diversity and marked population differentiation in some Altaic speakers. Sympatry eroded inter-ethnic differentiation. No regular decline in genetic similarity with geography was seen. CONCLUSION: Two layers of overall diversity represent a main feature of the genetic landscape of the population of the European portion of Russia.

Kinase-independent inhibition of cyclophosphamide-induced pathways protects the ovarian reserve and prolongs fertility.

Premature ovarian failure and infertility are adverse effects of cancer therapies. The mechanism underlying chemotherapy-mediated depletion of the ovarian reserve remains unclear. Here, we aim to identify the signaling pathways involved in the loss of the ovarian reserve to prevent the damaging effects of chemotherapy. We evaluated the effects of cyclophosphamide, one of the most damaging chemotherapeutic drugs, against follicle reserve. In vivo studies showed that the cyclophosphamide-induced loss of ovarian reserve occurred through a sequential mechanism. Cyclophosphamide exposure induced the activation of both DNAPK-γH2AX-checkpoint kinase 2 (CHK2)-p53/TAp63α isoform and protein kinase B (AKT)-forkhead box O3 (FOXO3a) signaling axes in the nucleus of oocytes. Concomitant administration of an allosteric ABL inhibitor and cyclophosphamide modulated both pathways while protecting the ovarian reserve from chemotherapy assaults. As a consequence, the fertility of the treated mice was prolonged. On the contrary, the administration of an allosteric ABL activator enhanced the lethal effects of cyclophosphamide while shortening mouse fertility. Therefore, kinase-independent inhibition may serve as an effective ovarian-protective strategy in women under chemotherapy.

P53 and Sirt1: routes of metabolism and genome stability.

The tumor suppressor p53 is a transcription factor that regulates key processes. But, the outcomes of the p53 response go beyond its role as a nuclear transcription factor. Sirtuin (SIRT1) regulates p53 functions as transcription factor. At the same time, SIRT1 protects the genome under stress conditions. The link between p53 and SIRT1 responses is unique. Both regulate metabolism, stress signaling, cell survival, cell cycle control and genome stability. Recent studies have proposed cancer as a metabolic disease. This is due to the switch from aerobic to anaerobic metabolism during tumor development. Yet, the complex molecular circuits (in and out of the nucleus) of tumor progression remain elusive. In this review, we will focus on the interplay between p53 and SIRT1. We will discuss their roles as nodes for possible therapeutic intervention.