Germ Lines and Fertility

Lead Research Organisation: MRC Human Genetics Unit

Abstract

Infertility affects about one in 6 couples and about half of cases are thought to have a genetic cause. Some cases can be treated successfully by in vitro fertilisation but this is expensive, not always available without high cost to the individual, and involves hormone treatments and minor surgery. In men one major genetic cause of infertility is loss of genes from the male Y chromosome. We are trying to understand what some of these and other genes involved do in fertile people with the aim of better understanding what goes wrong in those with fertility problems. To do this we use a range of different types of experiments. Some are designed to work out how chromosomes are assembled during the early stages of making sperm and eggs. Some of these experiments are test tube based. Others experiments can only be done by making changes in the mouse gene equivalent to the human gene we are interested in. Then we have a so-called mouse model and by studying these animals we can make predictions about the effects expected in humans. To reduce the use of animals in this work we are also trying to develop methods based on growing cells from mouse sperm and egg-making tissues in test tubes.

Technical Summary

Infertility affects between 12 and 15% of couples and although not life threatening it causes substantial distress. A major industry has developed around treatments such as IVF because of this but the causes of many, probably most, cases remain unknown and untreatable. Even so IVF births now account for 1.5% of live births in some countries (Fauser 2002, Ned. Tijdschr. Geneeskd. 146 2335-2338). Environmental, sociological and genetic causes all contribute to infertility and many estimates put the genetic contribution at around 50%. Model organism based studies suggest that a large number of genes are essential for spermatogenesis in particular (Hackstein et al. 2000, Trends Genet., 16 565-572). Paradoxically relatively few genes are known to be essential solely for spermatogenesis in humans. The Y chromosome is thought to be a favoured site for locating genes required for spermatogenesis and deletions of the Y chromosome facilitated by its content of segmental duplications are the single major genetic cause of male infertility known (Page et al. 1997, Biology Of Reproduction, 56 M12). We are working on the role of the autosomal ancestor of the Y chromosome gene DAZ. In mouse the Dazl gene is required for both male and female fertility, acting in the progenitors of meiotic germ cells. Our work suggests that the protein acts as a translational regulator of specific messages in germ cells. Dazl is one of the earliest markers of differentiation in mouse ES cells and we are manipulating murine ES cells to provide a model system in which they can reproducibly be differentiated into germ cells. In addition we are investigating the biology of selected DAZL RNA targets with particular attention to those shared between germ cells and embryonic stem cells.||A second class of genes we are investigating are novel components of the synaptonemal complex. These genes encode proteins which interact with known proteins of the synaptonemal complex and are required for complete synapsis. In their absence meiosis fails, genetic crossover does not take place and both male and female animals are infertile. They may also influence recombination frequencies and sites. We have defined the phenotype of null mutations of these genes using standard knockout technology and we will now search for more interacting proteins using two hybrid and immunoprecipitation methods and refine our knowledge of interactions to develop a structure for the central element of the SC. In particular we want to understand the relationship of these proteins, which are candidate infertility genes in humans, with the enzymes involved in recombination.
 
Title Syce1 ko 
Description Syce1ko mouse 
Type Of Material Model of mechanisms or symptoms - mammalian in vivo 
Year Produced 2009 
Provided To Others? Yes  
Impact not yet 
 
Title Syce2ko 
Description Syce2ko mouse 
Type Of Material Model of mechanisms or symptoms - mammalian in vivo 
Year Produced 2009 
Provided To Others? Yes  
Impact None yet 
 
Description CCMB 
Organisation Council of Scientific and Industrial Research (CSIR)
Department Centre for Cellular and Molecular Biology (CCMB)
Country India 
Sector Academic/University 
PI Contribution Provided techical expertise and equipment
Collaborator Contribution Provided access to samples and manpower for analysis
Impact Disproved hyposthesis
Start Year 2008
 
Description Karolinska 
Organisation Karolinska Institute
Country Sweden 
Sector Academic/University 
PI Contribution Provided KO animal and analysis
Collaborator Contribution Provision of antibodies data analysis
Impact 15944401
Start Year 2006
 
Description TuDresden 
Organisation Technical University of Dresden
Country Germany 
Sector Academic/University 
PI Contribution We have provided GM mice produced here and exchanged antibodies
Collaborator Contribution Publication - provision of materials
Impact 19851446
Start Year 2008
 
Description UoWurzburg 
Organisation University of Wurzburg
Country Germany 
Sector Academic/University 
PI Contribution Exchange of materials
Collaborator Contribution Will produce publication and provide information in advance
Impact 17339376
Start Year 2007
 
Description Utrecht 
Organisation Utrecht University
Country Netherlands 
Sector Academic/University 
PI Contribution Provided biological samples
Collaborator Contribution Data analysis
Impact 17339376
Start Year 2006