High-coverage genome of the Tyrolean Iceman reveals unusually high Anatolian farmer ancestry

The Tyrolean Iceman is known as one of the oldest human glacier mummies, directly dated to 3350-3120 calibrated BCE. A previously published low-coverage genome provided novel insights into European prehistory, despite high present-day DNA contamination. Here, we generate a high-coverage genome with low contamination (15.3×) to gain further insights into the genetic history and phenotype of this individual. Contrary to previous studies, we found no detectable Steppe-related ancestry in the Iceman. Instead, he retained the highest Anatolian-farmer-related ancestry among contemporaneous European populations, indicating a rather isolated Alpine population with limited gene flow from hunter-gatherer-ancestry-related populations. Phenotypic analysis revealed that the Iceman likely had darker skin than present-day Europeans and carried risk alleles associated with male-pattern baldness, type 2 diabetes, and obesity-related metabolic syndrome. These results corroborate phenotypic observations of the preserved mummified body, such as high pigmentation of his skin and the absence of hair on his head

(Micro)evolutionary changes and the evolutionary potential of bird migration

Seasonal migration is the yearly long-distance movement of individuals between their breeding and wintering grounds. Individuals from nearly every animal group exhibit this behavior, but probably the most iconic migration is carried out by birds, from the classic V-shape formation of geese on migration to the amazing nonstop long-distance flights undertaken by Arctic Terns Sterna paradisaea. In this chapter, we discuss how seasonal migration has shaped the field of evolution. First, this behavior is known to turn on and off quite rapidly, but controversy remains concerning where this behavior first evolved geographically and whether the ancestral state was sedentary or migratory (Fig. 7.1d, e). We review recent work using new analytical techniques to provide insight into this topic. Second, it is widely accepted that there is a large genetic basis to this trait, especially in groups like songbirds that migrate alone and at night precluding any opportunity for learning. Key hypotheses on this topic include shared genetic variation used by different populations to migrate and only few genes being involved in its control. We summarize recent work using new techniques for both phenotype and genotype characterization to evaluate and challenge these hypotheses. Finally, one topic that has received less attention is the role these differences in migratory phenotype could play in the process of speciation. Specifically, many populations breed next to one another but take drastically different routes on migration (Fig. 7.2). This difference could play an important role in reducing gene flow between populations, but our inability to track most birds on migration has so far precluded evaluations of this hypothesis. The advent of new tracking techniques means we can track many more birds with increasing accuracy on migration, and this work has provided important insight into migration's role in speciation that we will review here

Targeted Deficiency of the Transcriptional Activator Hnf1α Alters Subnuclear Positioning of Its Genomic Targets

DNA binding transcriptional activators play a central role in gene-selective regulation. In part, this is mediated by targeting local covalent modifications of histone tails. Transcriptional regulation has also been associated with the positioning of genes within the nucleus. We have now examined the role of a transcriptional activator in regulating the positioning of target genes. This was carried out with primary β-cells and hepatocytes freshly isolated from mice lacking Hnf1α, an activator encoded by the most frequently mutated gene in human monogenic diabetes (MODY3). We show that in Hnf1a−/− cells inactive endogenous Hnf1α-target genes exhibit increased trimethylated histone H3-Lys27 and reduced methylated H3-Lys4. Inactive Hnf1α-targets in Hnf1a−/− cells are also preferentially located in peripheral subnuclear domains enriched in trimethylated H3-Lys27, whereas active targets in wild-type cells are positioned in more central domains enriched in methylated H3-Lys4 and RNA polymerase II. We demonstrate that this differential positioning involves the decondensation of target chromatin, and show that it is spatially restricted rather than a reflection of non-specific changes in the nuclear organization of Hnf1a-deficient cells. This study, therefore, provides genetic evidence that a single transcriptional activator can influence the subnuclear location of its endogenous genomic targets in primary cells, and links activator-dependent changes in local chromatin structure to the spatial organization of the genome. We have also revealed a defect in subnuclear gene positioning in a model of a human transcription factor disease

The radial arrangement of the human chromosome 7 in the lymphocyte cell nucleus is associated with chromosomal band gene density

This is the author's accepted manuscript. The final published article is available from the link below. Copyright @ Springer-Verlag 2008.In the nuclei of human lymphocytes, chromosome territories are distributed according to the average gene density of each chromosome. However, chromosomes are very heterogeneous in size and base composition, and can contain both very gene-dense and very gene-poor regions. Thus, a precise analysis of chromosome organisation in the nuclei should consider also the distribution of DNA belonging to the chromosomal bands in each chromosome. To improve our understanding of the chromatin organisation, we localised chromosome 7 DNA regions, endowed with different gene densities, in the nuclei of human lymphocytes. Our results showed that this chromosome in cell nuclei is arranged radially with the gene-dense/GC-richest regions exposed towards the nuclear interior and the gene-poorest/GC-poorest ones located at the nuclear periphery. Moreover, we found that chromatin fibres from the 7p22.3 and the 7q22.1 bands are not confined to the territory of the bulk of this chromosome, protruding towards the inner part of the nucleus. Overall, our work demonstrates the radial arrangement of the territory of chromosome 7 in the lymphocyte nucleus and confirms that human genes occupy specific radial positions, presumably to enhance intra- and inter-chromosomal interaction among loci displaying a similar expression pattern, and/or similar replication timing

The role of historical and contemporary processes on phylogeographic structure and genetic diversity in the Northern Cardinal, Cardinalis cardinalis

Background Earth history events such as climate change are believed to have played a major role in shaping patterns of genetic structure and diversity in species. However, there is a lag between the time of historical events and the collection of present-day samples that are used to infer contemporary population structure. During this lag phase contemporary processes such as dispersal or non-random mating can erase or reinforce population differences generated by historical events. In this study we evaluate the role of both historical and contemporary processes on the phylogeography of a widespread North American songbird, the Northern Cardinal, Cardinalis cardinalis. Results Phylogenetic analysis revealed deep mtDNA structure with six lineages across the species\u27 range. Ecological niche models supported the same geographic breaks revealed by the mtDNA. A paleoecological niche model for the Last Glacial Maximum indicated that cardinals underwent a dramatic range reduction in eastern North America, whereas their ranges were more stable in México. In eastern North America cardinals expanded out of glacial refugia, but we found no signature of decreased genetic diversity in areas colonized after the Last Glacial Maximum. Present-day demographic data suggested that population growth across the expansion cline is positively correlated with latitude. We propose that there was no loss of genetic diversity in areas colonized after the Last Glacial Maximum because recent high-levels of gene flow across the region have homogenized genetic diversity in eastern North America. Conclusion We show that both deep historical events as well as demographic processes that occurred following these events are critical in shaping genetic pattern and diversity in C. cardinalis. The general implication of our results is that patterns of genetic diversity are best understood when information on species history, ecology, and demography are considered simultaneously

The role of historical and contemporary processes on phylogeographic structure and genetic diversity in the Northern Cardinal, Cardinalis cardinalis

<p>Abstract</p> <p>Background</p> <p>Earth history events such as climate change are believed to have played a major role in shaping patterns of genetic structure and diversity in species. However, there is a lag between the time of historical events and the collection of present-day samples that are used to infer contemporary population structure. During this lag phase contemporary processes such as dispersal or non-random mating can erase or reinforce population differences generated by historical events. In this study we evaluate the role of both historical and contemporary processes on the phylogeography of a widespread North American songbird, the Northern Cardinal, <it>Cardinalis cardinalis</it>.</p> <p>Results</p> <p>Phylogenetic analysis revealed deep mtDNA structure with six lineages across the species' range. Ecological niche models supported the same geographic breaks revealed by the mtDNA. A paleoecological niche model for the Last Glacial Maximum indicated that cardinals underwent a dramatic range reduction in eastern North America, whereas their ranges were more stable in México. In eastern North America cardinals expanded out of glacial refugia, but we found no signature of decreased genetic diversity in areas colonized after the Last Glacial Maximum. Present-day demographic data suggested that population growth across the expansion cline is positively correlated with latitude. We propose that there was no loss of genetic diversity in areas colonized after the Last Glacial Maximum because recent high-levels of gene flow across the region have homogenized genetic diversity in eastern North America.</p> <p>Conclusion</p> <p>We show that both deep historical events as well as demographic processes that occurred following these events are critical in shaping genetic pattern and diversity in <it>C. cardinalis</it>. The general implication of our results is that patterns of genetic diversity are best understood when information on species history, ecology, and demography are considered simultaneously.</p

Changes in chromatin structure during processing of wax-embedded tissue sections

The use of immunofluorescence (IF) and fluorescence in situ hybridisation (FISH) underpins much of our understanding of how chromatin is organised in the nucleus. However, there has only recently been an appreciation that these types of study need to move away from cells grown in culture and towards an investigation of nuclear organisation in cells in situ in their normal tissue architecture. Such analyses, however, especially of archival clinical samples, often requires use of formalin-fixed paraffin wax-embedded tissue sections which need addition steps of processing prior to IF or FISH. Here we quantify the changes in nuclear and chromatin structure that may be caused by these additional processing steps. Treatments, especially the microwaving to reverse fixation, do significantly alter nuclear architecture and chromatin texture, and these must be considered when inferring the original organisation of the nucleus from data collected from wax-embedded tissue sections

Actomyosin and vimentin cytoskeletal networks regulate nuclear shape, mechanics and chromatin organization

This work was supported in part by a Marie Curie CIG grant (PCIG14-GA-2013-631011 CSKFingerprints) and a BBSRC grant (BB/P006108/1). MCK is supported by a PhD studentship from the Life Sciences Initiative at QMUL

More mentoring needed? A cross-sectional study of mentoring programs for medical students in Germany

<p>Abstract</p> <p>Background</p> <p>Despite increasing recognition that mentoring is essential early in medical careers, little is known about the prevalence of mentoring programs for medical students. We conducted this study to survey all medical schools in Germany regarding the prevalence of mentoring programs for medical students as well as the characteristics, goals and effectiveness of these programs.</p> <p>Methods</p> <p>A definition of mentoring was established and program inclusion criteria were determined based on a review of the literature. The literature defined mentoring as a steady, long-lasting relationship designed to promote the mentee's overall development. We developed a questionnaire to assess key characteristics of mentoring programs: the advocated mentoring model, the number of participating mentees and mentors, funding and staff, and characteristics of mentees and mentors (e.g., level of training). In addition, the survey characterized the mentee-mentor relationship regarding the frequency of meetings, forms of communication, incentives for mentors, the mode of matching mentors and mentees, and results of program evaluations. Furthermore, participants were asked to characterize the aims of their programs. The questionnaire consisted of 34 questions total, in multiple-choice (17), numeric (7) and free-text (10) format. This questionnaire was sent to deans and medical education faculty in Germany between June and September 2009. For numeric answers, mean, median, and standard deviation were determined. For free-text items, responses were coded into categories using qualitative free text analysis.</p> <p>Results</p> <p>We received responses from all 36 medical schools in Germany. We found that 20 out of 36 medical schools in Germany offer 22 active mentoring programs with a median of 125 and a total of 5,843 medical students (6.9 - 7.4% of all German medical students) enrolled as mentees at the time of the survey. 14 out of 22 programs (63%) have been established within the last 2 years. Six programs (27%) offer mentoring in a one-on-one setting. 18 programs (82%) feature faculty physicians as mentors. Nine programs (41%) involve students as mentors in a peer-mentoring setting. The most commonly reported goals of the mentoring programs include: establishing the mentee's professional network (13 programs, 59%), enhancement of academic performance (11 programs, 50%) and counseling students in difficulties (10 programs, 45%).</p> <p>Conclusions</p> <p>Despite a clear upsurge of mentoring programs for German medical students over recent years, the overall availability of mentoring is still limited. The mentoring models and goals of the existing programs vary considerably. Outcome data from controlled studies are needed to compare the efficiency and effectiveness of different forms of mentoring for medical students.</p

Mentoring programs for medical students - a review of the PubMed literature 2000 - 2008

Abstract Background Although mentoring is acknowledged as a key to successful and satisfying careers in medicine, formal mentoring programs for medical students are lacking in most countries. Within the framework of planning a mentoring program for medical students at Zurich University, an investigation was carried out into what types of programs exist, what the objectives pursued by such programs are, and what effects are reported. Methods A PubMed literature search was conducted for 2000 - 2008 using the following keywords or their combinations: mentoring, mentoring program, medical student, mentor, mentee, protégé, mentorship. Although a total of 438 publications were identified, only 25 papers met the selection criteria for structured programs and student mentoring surveys. Results The mentoring programs reported in 14 papers aim to provide career counseling, develop professionalism, increase students' interest in research, and support them in their personal growth. There are both one-to-one and group mentorships, established in the first two years of medical school and continuing through graduation. The personal student-faculty relationship is important in that it helps students to feel that they are benefiting from individual advice and encourages them to give more thought to their career choices. Other benefits are an increase in research productivity and improved medical school performance in general. Mentored students also rate their overall well-being as higher. - The 11 surveys address the requirements for being an effective mentor as well as a successful mentee. A mentor should empower and encourage the mentee, be a role model, build a professional network, and assist in the mentee's personal development. A mentee should set agendas, follow through, accept criticism, and be able to assess performance and the benefits derived from the mentoring relationship. Conclusion Mentoring is obviously an important career advancement tool for medical students. In Europe, more mentoring programs should be developed, but would need to be rigorously assessed based on evidence of their value in terms of both their impact on the career paths of juniors and their benefit for the mentors. Medical schools could then be monitored with respect to the provision of mentorships as a quality characteristic.</p