Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

Breast cancer management pathways during the COVID-19 pandemic: outcomes from the UK ‘Alert Level 4’ phase of the B-MaP-C study

Abstract: Background: The B-MaP-C study aimed to determine alterations to breast cancer (BC) management during the peak transmission period of the UK COVID-19 pandemic and the potential impact of these treatment decisions. Methods: This was a national cohort study of patients with early BC undergoing multidisciplinary team (MDT)-guided treatment recommendations during the pandemic, designated ‘standard’ or ‘COVID-altered’, in the preoperative, operative and post-operative setting. Findings: Of 3776 patients (from 64 UK units) in the study, 2246 (59%) had ‘COVID-altered’ management. ‘Bridging’ endocrine therapy was used (n = 951) where theatre capacity was reduced. There was increasing access to COVID-19 low-risk theatres during the study period (59%). In line with national guidance, immediate breast reconstruction was avoided (n = 299). Where adjuvant chemotherapy was omitted (n = 81), the median benefit was only 3% (IQR 2–9%) using ‘NHS Predict’. There was the rapid adoption of new evidence-based hypofractionated radiotherapy (n = 781, from 46 units). Only 14 patients (1%) tested positive for SARS-CoV-2 during their treatment journey. Conclusions: The majority of ‘COVID-altered’ management decisions were largely in line with pre-COVID evidence-based guidelines, implying that breast cancer survival outcomes are unlikely to be negatively impacted by the pandemic. However, in this study, the potential impact of delays to BC presentation or diagnosis remains unknown

Bridging pre-surgical endocrine therapy for breast cancer during the COVID-19 pandemic: outcomes from the B-MaP-C study

Purpose: The B-MaP-C study investigated changes to breast cancer care that were necessitated by the COVID-19 pandemic. Here we present a follow-up analysis of those patients commenced on bridging endocrine therapy (BrET), whilst they were awaiting surgery due to reprioritisation of resources. Methods: This multicentre, multinational cohort study recruited 6045 patients from the UK, Spain and Portugal during the peak pandemic period (Feb–July 2020). Patients on BrET were followed up to investigate the duration of, and response to, BrET. This included changes in tumour size to reflect downstaging potential, and changes in cellular proliferation (Ki67), as a marker of prognosis. Results: 1094 patients were prescribed BrET, over a median period of 53 days (IQR 32–81 days). The majority of patients (95.6%) had strong ER expression (Allred score 7–8/8). Very few patients required expedited surgery, due to lack of response (1.2%) or due to lack of tolerance/compliance (0.8%). There were small reductions in median tumour size after 3 months’ treatment duration; median of 4 mm [IQR − 20, 4]. In a small subset of patients ( n = 47), a drop in cellular proliferation (Ki67) occurred in 26 patients (55%), from high (Ki67 ≥ 10%) to low (< 10%), with at least one month’s duration of BrET. Discussion: This study describes real-world usage of pre-operative endocrine therapy as necessitated by the pandemic. BrET was found to be tolerable and safe. The data support short-term (≤ 3 months) usage of pre-operative endocrine therapy. Longer-term use should be investigated in future trials

High-Resolution Landmark Framework for the Sequence-Ready Mapping of Xq23–q26.1

We have established a landmark framework map over 20–25 Mb of the long arm of the human X chromosome using yeast artificial chromosome (YAC) clones. The map has approximately one landmark per 45 kb of DNA and stretches from DXS7531 in proximal Xq23 to DXS895 in proximal Xq26, connecting to published framework maps on its proximal and distal sides. There are three gaps in the framework map resulting from the failure to obtain clone coverage from the YAC resources available. Estimates of the maximum sizes of these gaps have been obtained. The four YAC contigs have been positioned and oriented using somatic-cell hybrids and fluorescence in situ hybridization, and the largest is estimated to cover ∼15 Mb of DNA. The framework map is being used to assemble a sequence-ready map in large-insert bacterial clones, as part of an international effort to complete the sequence of the X chromosome. PAC and BAC contigs currently cover 18 Mb of the region, and from these, 12 Mb of finished sequence is available.</jats:p

The DNA sequence of the human X chromosome

The human X chromosome has a unique biology that was shaped by its evolution as the sex chromosome shared by males and females. We have determined 99.3% of the euchromatic sequence of the X chromosome. Our analysis illustrates the autosomal origin of the mammalian sex chromosomes, the stepwise process that led to the progressive loss of recombination between X and Y, and the extent of subsequent degradation of the Y chromosome. LINE1 repeat elements cover one-third of the X chromosome, with a distribution that is consistent with their proposed role as way stations in the process of X-chromosome inactivation. We found 1,098 genes in the sequence, of which 99 encode proteins expressed in testis and in various tumour types. A disproportionately high number of mendelian diseases are documented for the X chromosome. Of this number, 168 have been explained by mutations in 113 X-linked genes, which in many cases were characterized with the aid of the DNA sequence