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Professor Nabeel Affara

Professor Nabeel Affara

Professor of Molecular Genetics and Genomics

Department of Pathology
University of Cambridge
Tennis Court Road
Cambridge
CB2 1QP

Office Phone: +44 (0)1223 333700

Research themes

Genomics:

Research Interests

Professor Affara's group has research interests in three main areas

affara-mouse-sperm
Figure 1 Mouse sperm nuclei stained with DAPI. The pink signal is from in situ hybridization of a Y specific DNA probe to the Y chromosome.
The Molecular Genetics and Genomics of Mammalian Sex Chromosomes and Spermatogenesis:  The mapping and sequencing of the mammalian sex chromosomes has been a longstanding interest with a particular focus on X-Y homologous genes potentially involved in male fertility and cognitive behaviour. Studies in mouse have identified novel families of amplified genes on both sex chromosomes, uncovering a genomic conflict between the X and Y genomes that plays an important role in maintaining sex ratios. Analysis of the porcine sex chromosomes has led to the first map of the pig Y and an understanding of its gene content and sequence organisation relative to other mammalian Y chromosomes and the pig X. These studies have been combined with transcriptional analysis of the first pre-pubertal wave of spermatogenesis using microarray and RNAseq approaches to identify key pathways and genes involved in germ cell differentiation.


Porcine Maternal Infanticide as a Model for Human Puerperal Psychosis:
Savaging of newborn piglets by the sow within 24 hours of birth shares a number behavioural similarities with the extreme form of neglect of and aggression towards the newborn in humans known as puerperal psychosis. This is a psychotic behaviour at the extreme end of the spectrum of adverse human maternal behaviour and clustering in families has indicated that there is an important genetic contribution.

affara-porcine
Figure 2 Good porcine mothering behaviour in the immediate postnatal period. Passive presentation of teats.
 group has been investigating a porcine model of this behaviour where there is considerable variation in incidence between breeds. This also indicates an important genetic contribution. In order to understand the genetic and epigenetic correlates that contribute to this maternal aggression, the group has been conducting (a) detailed genome scans to map genetic loci associated with the behaviour, (b) expression studies on brain tissue (hypothalamus, the key region of the brain influencing maternal behaviour)) to identify gene expression differences between aggressive and non-aggressive sows and (c) epigenetic studies to determine whether differential DNA methylation may also be involved in the aberrant maternal behaviour. As might be expected, this is a complex behaviour that is likely to involve multiple genes and this is borne out by the genome-wide association studies. Current work is focussed on assessing DNA sequence and methylation variation in candidate genomic intervals and, through the use of RNAseq, detailed analysis of expression profiles not only for coding but also non-coding RNA species. The identification of important genes and transcripts in the porcine model offers strong candidates for examination of the human condition.


Developmental Origins of Health and Disease: It is increasingly being appreciated from human and animal model studies that genome-environment interactions play a key role in the development of disease processes. This has lead to the DOHAD (Developmental Origins of Health and Disease) hypothesis that proposes a key role for early life (intrauterine and early postnatal development) exposures (pathogen, nutritional, chemical and behavioural) of tissues and individual cell types in leading to chronic non-communicable disease in later life. affara-foetusThere is an increasing weight of evidence that intrauterine and early postnatal exposures at critical times of growth and development place offspring on a disease trajectory of increased risk of chronic disease and that this is mediated by alteration of gene activity in important genetic pathways through stable epigenetic modification of DNA and chromatin.

affara-epigentic-dna
Figure 3 The common epigenetic DNA modification represented by methylation of cytosine.
Consequently, a key part of understanding disease processes is focused on unpicking the role(s) played by epigenetic modification of chromatin and DNA and the mechanisms involved in transducing environmental exposures leading 
to stable epigenetic changes that place the individual on a disease trajectory. In collaboration with colleagues in the Department of Paediatrics, the London School of Hygiene and Tropical Medicine and the MRC Unit The Gambia we are exploring epigenetic and transcriptional (using DNA methylation, histone modification and RNAseq analysis) correlates of periconceptional and postnatal nutritional deficits, placental malaria infection leading to restricted foetal growth, stunting and altered immune function in the newborn. The aim of such studies is the design of appropriately timed nutritional and immunological interventions to avoid adverse clinical outcomes in later life. 

Embedded within the group is the Departmental Genomics Facility, Cambridge Genomics Services

Senior Research Scientists:
Dr. Carole Sargent, Dr. Claire Quilter, Dr. Benjamin Skinner

Computational Biologists:
Julian Bauer and Maria Gomez

Research Technicians and Research Assistants:
Kerry Harvey, Kim Lachani and Joanne Bacon

Ph.D. Students:
Courtney Landers, Emma Johnson and Julian Bauer.


Key Publications

1. Khulan B, Cooper WN, Skinner BM, Bauer J, Owens S, Prentice AM, Belteki G,Constancia M, Dunger D,  and Affara NA (2012). Periconceptional maternal micronutrient supplementation is associated with widespread gender related changes in the epigenome: a study of a unique resource in the Gambia. Hum Mol Genet. 21(9):2086-101.

2. Cooper WN, Khulan B, Owens S, Elks CE, Seidel V, Prentice AM, Belteki G, Ong KK, Affara NA, Constância M, Dunger DB (2012). DNA methylation profiling at imprinted loci after periconceptional micronutrient supplementation in humans: results of a pilot randomized controlled trial. FASEB J. 26(5):1782-90.

3. Quilter CR, Sargent CA, Bauer J, Bagga M, Reiter C, Hutchinson E, Southwood O, Evans G, Mileham, A, Griffin D and Affara NA (2012). An association and haplotype analysis of porcine maternal infanticide: A model for human puerperal psychosis? Am. J. Med. Genet., B Neuropsychiatr. Genet. 159B, 908-927.

4. Cocquet J, Ellis PJI, Mahadevaiah, SK, Affara NA, Vaiman D and Burgoyne P (2012). A genetic basis for a postmeiotic X vs, Y chromosome intragenomic conflict in the mouse. PLoS Genetics, 8(9):e1002900

5. Skinner, BM, Lachani K, Sargent CA, Affara, NA (2013). Regions of XY homology in the pig X chromosome and the boundary of the pseudoautosomal region. BMC Genetics, Jan 15;14:3. doi: 10.1186/1471-2156-14-3.

6. Quilter CR, Cooper WN, Cliffe KM, Skinner BM, Prentice PM, Nelson L, Bauer J, Ong KK, Constância M, Lowe WL, Affara NA, Dunger DB. Impact on offspring methylation patterns of maternal gestational diabetes mellitus and intrauterine growth restraint suggest common genes and pathways linked to subsequent type 2 diabetes risk. FASEB J. 2014 Nov;28(11):4868-79. doi: 10.1096/fj.14-255240. Epub  2014 Aug 21. PubMed PMID: 25145626.

7. Benjamin M. Skinner1*, Carole A. Sargent1*, Carol Churcher2,6*, Toby Hunt2, Javier Herrero3,4, Jane Loveland2, Matt Dunn2, Sandra Louzada2, Beiyuan Fu2, Will Chow2, James Gilbert2, Siobhan Austin-Guest2, Kathryn Beal3, Denise Carvalho-Silva3, William Cheng2, Daria Gordon2, Darren Grafham2,7, Matt Hardy2, Jo Harley2, Heidi Hauser2, Philip Howden1,2, Kerstin Howe2, Kim Lachani1, Peter J.I. Ellis1,5, Daniel Kelly2, Giselle Kerry2, James Kerwin2, Bee Ling Ng2, William Cheng2, Glen Threadgold2, Thomas Wileman2, Jo Wood2, Fengtang Yang2, Jen Harrow2, Nabeel A. Affara1, Chris Tyler-Smith2,8 (2015) The pig X and Y chromosomes: structure, sequence and evolution. Genomic Research, accepted and under revision.

8. Benjamin M Skinner, Kim Lachani, Carole A Sargent, Fengtang Yang, Peter Ellis, Toby Hunt, Beiyuan Fu, Sandra Louzada, Carol Churcher, Chris Tyler-Smith and Nabeel A Affara. (2015). Expansion of the HSFY gene family in pig lineages. BMC Genomics in press.