Mouse models in the era of large human tumour sequencing studies.

Cancer is a complex disease in which cells progressively accumulate mutations disrupting their cellular processes. A fraction of these mutations drive tumourigenesis by affecting oncogenes or tumour suppressor genes, but many mutations are passengers with no clear contribution to tumour development. The advancement of DNA and RNA sequencing technologies has enabled in-depth analysis of thousands of human tumours from various tissues to perform systematic characterization of their (epi)genomes and transcriptomes in order to identify (epi)genetic changes associated with cancer. Combined with considerable progress in algorithmic development, this expansion in scale has resulted in the identification of many cancer-associated mutations, genes and pathways that are considered to be potential drivers of tumour development. However, it remains challenging to systematically identify drivers affected by complex genomic rearrangements and drivers residing in non-coding regions of the genome or in complex amplicons or deletions of copy-number driven tumours. Furthermore, functional characterization is challenging in the human context due to the lack of genetically tractable experimental model systems in which the effects of mutations can be studied in the context of their tumour microenvironment. In this respect, mouse models of human cancer provide unique opportunities for pinpointing novel driver genes and their detailed characterization. In this review, we provide an overview of approaches for complementing human studies with data from mouse models. We also discuss state-of-the-art technological developments for cancer gene discovery and validation in mice.

Observation of tool use and modification for apparent hygiene purposes in a mandrill.

Tool making or modification to produce a tool of apparent improved functionality has rarely been reported in monkeys, especially when tools are used outside the context of food acquisition. We report on an observation of selection, modification and use of splinters for hygiene purposes in a male mandrill. The zoo-housed animal was video-recorded breaking splinters in sequence to use them underneath his toenails. This record brings forward new evidence that the ability to use and modify tools is not limited to apes and some New World monkeys but is also apparent in Old Word monkeys.

Male dominance rank, mating and reproductive success in captive bonobos (Pan paniscus).

In the recent past, application of DNA genotyping techniques has enabled researchers to more accurately test relationships between dominance rank (DR), mating success (MS) and reproductive success (RS). Paternity studies often reveal that reproductive outcome does not always correlate with male DR and/or MS and thus open room for discussion and interpretation of alternative reproductive tactics of both sexes. In this study, we analysed male DR, MS and RS in a group of bonobos at Twycross Zoo (UK). Genetic relationships were determined using 8 tetrameric microsatellite loci. Despite clear and asymmetric dominance relationships, analysed using normalised David's scores based on a dyadic index of dominance among the group's 3 mature males, we found that the most dominant male did not sire the most offspring. In fact, both infants conceived during the observation period were found to be sired by the lower-ranking males. Although the alpha male had almost exclusive mating access to one of the females during the time she was showing a maximal anogenital swelling, her infant was sired by the lowest-ranking male who mostly mated with her when outside the maximal swelling period. This result suggests that either sperm competition operates and/or ovulation is decoupled from the phase of maximal anogenital swelling which could allow greater female choice.

Relatedness of matrilines, dispersing males and social groups in long-tailed macaques (Macaca fascicularis).

Genealogical relatedness is thought to be an important causal factor in the evolution of cooperation. We inferred relatedness on the basis of 11 blood protein markers using the Queller and Goodnight index of relatedness in a macaque population with long-term demographic records. This estimate reflected independently determined pedigree relationships in our data set. Mean relatedness among all members of a social group was 0.10 but much higher levels of relatedness (0.30-0.47) were found among the members of matrilineal families with a high or intermediate social rank. Groups of dispersing males that had been born into the same social group were sometimes closely related (0.43 and 0.58), but they could also be less related (0.08). We found that the pattern of distribution of relatedness was associated with gene flow and differential reproduction in males, rather than with group fission and the presence of geographical barriers.

Genetic structure of a population with social structure and migration.

Long-tailed macaques (Macaca fascicularis) live in social groups consisting of resident adult females and their offspring, and immigrant males. Subadult males leave their birth group, and might establish themselves as reproducing males in another group. Females do not leave their birth group. Such a social pattern might have consequences for the genetic differentiation between groups and the genetic relationships within groups. In a field study of long-tailed macaques (Macaca fascicularis) in Ketambe, Sumatra, Indonesia, blood samples were taken from individuals in seven adjacent social groups. Electrophoretic analysis showed 17 blood proteins and enzymes to be polymorphic, allowing the computation of heterozygosities and of the F-statistics. Of the F-statistics, F(IS) indicates the deviation from Hardy-Weinberg equilibrium averaged over local populations, FST indicates the differentiation in allele frequency between local populations, and F(IT) indicates the deviation from Hardy-Weinberg equilibrium over the total population. In a computer simulation of the population of long-tailed macaques using many loci with many neutral alleles, F(IS) and FST values proved to be characteristic for a certain demography and life history of the population, and proved not to depend upon the number of alleles or level of heterozygosity. FST values found in the simulation were compatible to those found in the field; in the simulation, values for F(IS) and F(IT) were consistently negative. The explanation for the negative F(IS) appears to be that genetic drift causes differentiation in allele frequencies between groups, and that due to this differentiation, allele frequencies differ between resident females and immigrant males, leading to offspring with an excess of heterozygotes (negative F(IS)) relative to the expectation based upon the overall allele frequency. The excess of heterozygotes might imply that slightly deleterious alleles are protected from selection. A population with a social structure and differential migration of the sexes is liable to accumulate deleterious recessives and, as a consequence, to be very sensitive to inbreeding on disruption of the social structure, as for instance in zoos.

Capturing wild long-tailed macaques (Macaca fascicularis).

Long-tailed macaques (Macaca fascicularis Raffles, 1821) were captured at various locations in the north of Sumatra as part of a study on social behaviour and genetic relationships. We used individual cage traps, a group trap, a blowpipe and an air-pressure rifle. Provided that the monkeys were willing to take bait, individual cage traps proved most successful; they gave a high capture rate with minimal disturbance of the group. Success with young juveniles and peripheral animals could be improved by placing elevated traps in the centre and in clusters at the periphery of the trapping site. Trapping had no clear lasting effect on the natural behaviour of the animals.