The Tyrolean Iceman, a 5,300-year-old Copper age individual, was discovered in 1991 on the Tisenjoch Pass in the Italian part of the Ötztal Alps. Here we report the complete genome sequence of the Iceman and show 100% concordance between the previously reported mitochondrial genome sequence and the consensus sequence generated from our genomic data. We present indications for recent common ancestry between the Iceman and presentday inhabitants of the Tyrrhenian sea, that the Iceman probably had brown eyes, belonged to blood group o and was lactose intolerant. His genetic predisposition shows an increased risk for coronary heart disease and may have contributed to the development of previously reported vascular calcifications. sequences corresponding to ~60% of the genome of Borrelia burgdorferi are indicative of the earliest human case of infection with the pathogen for Lyme borreliosis.

The stomach bacterium Helicobacter pylori is one of the most prevalent human pathogens. It has dispersed globally with its human host resulting in a distinct phylogeographic pattern that can be used to reconstruct both recent and ancient human migrations. The extant European population of H. pylori is known to be a hybrid between Asian and African bacteria, but there exist different hypotheses about when and where the hybridization took place, reflecting the complex demographic history of Europeans. Here, we present a 5,300-year-old H. pylori genome from a European Copper Age glacier mummy. The “Iceman” H. pylori is a nearly-pure representative of the bacterial population of Asian origin that existed in Europe prior to hybridization, suggesting the African population arrived in Europe within the last few thousand years.

not submitted for publication S-03 Abstract not submitted for publication S-04

Deleterious mutations of the BRCA1 and BRCA2 genes are a major risk factor for the development of breast and ovarian cancers. [1][2][3][4] Mutation tests for these two genes commonly are now offered in specialised clinics.5 6 As a result, a large number of women with personal or family histories of breast or ovarian cancer seek genetic counselling. Accurate evaluation of the probability that a woman carries a germline pathogenic mutation at BRCA1 or BRCA2 therefore is essential to help counsellors and those being counselled to decide whether testing is appropriate. In this context, the questions of practical interest are: Given the pedigree, what is the chance of a mutation being present? and What is the chance of the DNA laboratory finding a mutation?After testing became available, several models were developed to assess the pre-test probability of identifying carriers of mutations. Broadly speaking, two different approaches have been used to develop predictive models: the ''empirical approach'' and the ''Mendelian approach''.7 In empirical models, families are stratified according to variables that describe their family history; regression or other approaches are used to predict the results of Mendelian testing. In some cases, this approach simply consists of observing the proportion of mutations found in different strata. Mendelian models, in contrast, address the probability that a proband is a mutation carrier on the basis of explicit assumptions about the genetic parameters (allele frequencies and cancer penetrances in carriers and non-carriers) and the Mendelian rules of gene transmission. A consequence of the two different strategies is that the Mendelian models evaluate the probability that a proband is a gene carrier, whereas the empirical models evaluate the probability of identifying a mutation.The main purpose of this study was to compare the performances of published models in predicting mutation test results in a large dataset. We collected pedigrees of probands investigated for BRCA1 and BRCA2 mutations in five clinical centres included in the Italian Consortium for Hereditary Breast and Ovarian Cancer. The combined sample included 568 families. Among those, 80 pathogenic mutations were identified in the BRCA1 gene and 53 in the BRCA2 gene. Eight models were investigated: the University of Pennsylvania (Penn) model, the Myriad-1 model, the Myriad Tables, the Spanish model, the Finnish model, the Yale model, the Brcapro model, [8][9][10][11][12][13][14][15][16][17] and a novel model that we refer to as the Italian Consortium (IC) model, intended to be used as a research tool. The latter is based on the parameter values of Brcapro (with minor modifications) and is implemented in the Mlink program of the Fastlink package. 18Mutations of the two genes are associated with differences in familial presentations. BRCA1 is mutated preferentially in families with breast and ovarian cancer and more rarely is mutated in families with male breast cancer.19-21 BRCA2 was mapped primarily through families with m...

Accurate estimates of breast and ovarian cancer penetrance in BRCA1/2 mutation carriers are crucial in genetic counseling. Estimation is difficult because of the low frequency of mutated alleles and the oftenuncertain mechanisms of family ascertainment. We estimated the penetrances of breast and ovarian cancers in carriers of BRCA1/2 mutations by maximizing the retrospective likelihood of the genetic model, given the observed test results, in 568 Italian families screened for germline mutations. The software BRCAPRO was used as a probability calculation tool in a Markov Chain Monte Carlo approach. Breast cancer penetrances were 27% (95% CI 20-34%) at age 50 years and 39% (27 -52%) at age 70 in BRCA1 carriers, and 26% (0.18 -0.34%) at age 50 and 44% (29 -58%) at age 70 in BRCA2 carriers, and ovarian cancer penetrances were 14% (7-22%) at age 50 and 43% (21-66%) at age 70 in BRCA1 carriers and 3% (0 -7%) at age 50 and 15% (4-26%) at age 70 in BRCA2 carriers. The new model gave a better fit than the current default in BRCAPRO, the likelihood being 70 log units greater; in addition, the observed numbers of mutations in families stratified by gene and by cancer profile were not significantly different from those expected. Our new penetrance functions are appropriate for predicting breast cancer risk, and for determining the probability of carrying BRCA1/2 mutations, in people who are presently referred to genetic counseling in Italy. Our approach could lead to country-customized versions of the BRCAPRO software by providing appropriate population-specific estimates.