Genome sequencing of normal cells reveals developmental lineages and mutational processes

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Abstract

The somatic mutations present in the genome of a cell accumulate over the lifetime of a multicellular organism. These mutations can provide insights into the developmental lineage tree, the number of divisions that each cell has undergone and the mutational processes that have been operative. Here we describe whole genomes of clonal lines derived from multiple tissues of healthy mice. Using somatic base substitutions, we reconstructed the early cell divisions of each animal, demonstrating the contributions of embryonic cells to adult tissues. Differences were observed between tissues in the numbers and types of mutations accumulated by each cell, which likely reflect differences in the number of cell divisions they have undergone and varying contributions of different mutational processes. If somatic mutation rates are similar to those in mice, the results indicate that precise insights into development and mutagenesis of normal human cells will be possible.

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Chromatin organization is a major influence on regional mutation rates in human cancer cells.

Benjamin Schuster-Böckler, Ben Lehner (2012)

Cancer genome sequencing provides the first direct information on how mutation rates vary across the human genome in somatic cells. Testing diverse genetic and epigenetic features, here we show that mutation rates in cancer genomes are strikingly related to chromatin organization. Indeed, at the megabase scale, a single feature—levels of the heterochromatin-associated histone modification H3K9me3—can account for more than 40% of mutation-rate variation, and a combination of features can account for more than 55%. The strong association between mutation rates and chromatin organization is upheld in samples from different tissues and for different mutation types. This suggests that the arrangement of the genome into heterochromatin- and euchromatin-like domains is a dominant influence on regional mutation-rate variation in human somatic cells.

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Molecular phylogenetics: principles and practice.

Ziheng Yang, Bruce Rannala (2012)

Phylogenies are important for addressing various biological questions such as relationships among species or genes, the origin and spread of viral infection and the demographic changes and migration patterns of species. The advancement of sequencing technologies has taken phylogenetic analysis to a new height. Phylogenies have permeated nearly every branch of biology, and the plethora of phylogenetic methods and software packages that are now available may seem daunting to an experimental biologist. Here, we review the major methods of phylogenetic analysis, including parsimony, distance, likelihood and Bayesian methods. We discuss their strengths and weaknesses and provide guidance for their use.

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Oxygen as a friend and enemy: How to combat the mutational potential of 8-oxo-guanine.

Barbara van Loon, Enni Markkanen, Ulrich Hübscher (2010)

The maintenance of genetic stability is of crucial importance for any form of life. Prior to cell division in each mammalian cell, the process of DNA replication must faithfully duplicate the three billion bases with an absolute minimum of mistakes. Various environmental and endogenous agents, such as reactive oxygen species (ROS), can modify the structural properties of DNA bases and thus damage the DNA. Upon exposure of cells to oxidative stress, an often generated and highly mutagenic DNA damage is 7,8-dihydro-8-oxo-guanine (8-oxo-G). The estimated steady-state level of 8-oxo-G lesions is about 10(3) per cell/per day in normal tissues and up to 10(5) lesions per cell/per day in cancer tissues. The presence of 8-oxo-G on the replicating strand leads to frequent (10-75%) misincorporations of adenine opposite the lesion (formation of A:8-oxo-G mispairs), subsequently resulting in C:G to A:T transversion mutations. These mutations are among the most predominant somatic mutations in lung, breast, ovarian, gastric and colorectal cancers. Thus, in order to reduce the mutational burden of ROS, human cells have evolved base excision repair (BER) pathways ensuring (i) the correct and efficient repair of A:8-oxo-G mispairs and (ii) the removal of 8-oxo-G lesions from the genome. Very recently it was shown that MutY glycosylase homologue (MUTYH) and DNA polymerase lambda play a crucial role in the accurate repair of A:8-oxo-G mispairs. Here we review the importance of accurate BER of 8-oxo-G damage and its regulation in prevention of cancer. Copyright 2010 Elsevier B.V. All rights reserved.