The impact of sexual dimorphism on reproduction and health
Lead Research Organisation:
University of Edinburgh
Department Name: The Roslin Institute
Abstract
Abstracts are not currently available in GtR for all funded research. This is normally because the abstract was not required at the time of proposal submission, but may be because it included sensitive information such as personal details.
Technical Summary
In all livestock systems, one sex is more productive: male animals are often more suited for meat production, while female animals may be used for breeding stock, eggs and milk. In each case, the more productive sex is required in greater numbers. This is well illustrated by the poultry industry, where chicks of egg-laying strains are sexed on the day of hatch and only the females retained while poultry meat producers are forced to accept the relative inefficiency of raising an equal number of slower growing females (males outweigh females by as much as 35% at age of sale). Obviously, the capability to manipulate the sex-ratio of birds raised would be a major benefit to the poultry industry and significantly increase food production. For all livestock species, an ability to carry out sex selection and/or mitigate the impact of gender on productivity would substantially increase reproductive efficiency, reduce waste and alleviate welfare concerns associated with culling the less useful gender. This project aims to address these issues by applying our understanding of the mechanisms underlying sexual development to devise means of manipulating sex ratios, and to increase reproductive efficiency by improving follicle selection. Understanding of the processes controlling the generation of healthy sperm and oocytes lies at the core of fertility and we will determine key features of germ cell development to facilitate in vitro production of gametes.
Planned Impact
unavailable
Organisations
- University of Edinburgh (Lead Research Organisation)
- Francis Crick Institute (Collaboration)
- Genus plc (Collaboration)
- FAO/IAEA Agriculture and Biotechnology Laboratories (Collaboration)
- Zoetis (Collaboration)
- Guangxi University (Collaboration)
- Centre of Innovation Excellence in Livestock (Collaboration)
- Scotland's Rural College (Collaboration)
Publications
Ashworth CJ
(2013)
Genotype and fetal size affect maternal-fetal amino acid status and fetal endocrinology in Large White × Landrace and Meishan pigs.
in Reproduction, fertility, and development
Ashworth CJ
(2016)
Sex-specific prenatal stress effects on the rat reproductive axis and adrenal gland structure.
in Reproduction (Cambridge, England)
Campbell BK
(2012)
The role of anti-Müllerian hormone (AMH) during follicle development in a monovulatory species (sheep).
in Endocrinology
Ciccarelli M
(2020)
Donor-derived spermatogenesis following stem cell transplantation in sterile NANOS2 knockout males.
in Proceedings of the National Academy of Sciences of the United States of America
Donadeu FX
(2014)
Transcriptome profiling of granulosa and theca cells during dominant follicle development in the horse.
in Biology of reproduction
Donadeu FX
(2012)
Involvement of miRNAs in ovarian follicular and luteal development.
in The Journal of endocrinology
Donadeu FX
(2013)
Differential miRNA expression between equine ovulatory and anovulatory follicles.
in Domestic animal endocrinology
Donadeu FX
(2017)
A miRNA target network putatively involved in follicular atresia.
in Domestic animal endocrinology
Donadeu FX
(2016)
MicroRNA indicators of follicular steroidogenesis.
in Reproduction, fertility, and development
Garcia-Morales C
(2015)
Cell-autonomous sex differences in gene expression in chicken bone marrow-derived macrophages.
in Journal of immunology (Baltimore, Md. : 1950)
| Description | We have established that the mechanisms and factors that regulate the development of the sexual phenotype differ between mammals and birds. We have shown that, unlike mammals, avian somatic cells possess a cell-autonomous sex identity (CASI), and that CASI is the major determinant in defining the sexual phenotype. We have demonstrated that male and female cells respond differently to extracellular signals (hormonal and developmental). We have identified a set of genes that are expressed differently in male and female cells from the point of fertilisation through to adulthood. These genes are expressed in a sexually dimorphic fashion in all tissues at all stages of development, and are likely to represent the molecular signature underlying the inherent sex-identity that we identified in avian cells. We have shown that this inherent sex-identity can be 'short-circuited' by perturbing intracellular signals. Most significantly, we demonstrated that cells of the male and female immune systems are different: female cells are effectively pre-primed to respond to infection and this may account for the sex-related differences seen in mortality rates due to infection. Our recent work suggests that the molecular signals underlying cell autonomous sex identity are the result of tissue and sex-specific differences in the 'dosage compensation' of Z-chromosome genes. We have also identified morphological and molecular differences in the embryonic development of male and female skeletal muscle. We believe that establishing this sexual dimorphism during embryonic development is the key reason for the difference in muscle mass between sexually mature male and female birds. A thorough understanding of this mechanism may provide a means of selecting larger female birds and thereby increasing poultry meat production. We are using novel gene editing technology to mutate genes thought to be important in sex determination and in germ cell development. We have generated lines of birds for both gene mutations and are breeding these to homozygosity. We are currently assessing the morphological and molecular effects of these gene mutations on gonadal development. We have also identified sex differences in the expression of anorectic and orexigenic genes influencing appetite in the hypothalamus of chickens, which will advance our understanding of the difference in growth potential, and therefore productivity, of male and female chickens. From our genome-wide profiling studies in ruminants we have identified miRNA signatures associated with follicular-to-luteal differentiation in the ovary. In subsequent comparative studies in both cattle and humans we have identified a specific miRNA cluster (miR-183-96-182), that we have shown promotes cell survival and progesterone production by the corpus luteum, two functions that are key to successful establishment of pregnancy in these two species. We have performed pioneer studies (with support from a Case studentship and additional funding from Zoetis) to investigate the potential of miRNAs as biomarkers of reproductive status in farm animals using RNA sequencing. We have established methodologies to profile small RNAs in biofluids (plasma and follicular fluid) from these species and have identified specific miRNA signatures consistently associated with ovarian follicle health, the oestrous cycle and early pregnancy. We have identified changes in miRNA levels in circulation as early as day 8 of pregnancy in cattle, much early than any other molecular changes identified in previous studies. Since reliable methods for early pregnancy diagnosis in cattle are lacking and this is a major factor limiting productivity in dairy herds, our results aim to provide the means to increase reproductive efficiency and thus productivity in the dairy industry. In addition, the miRNAs we have identified in cattle that are linked to progesterone production may provide novel molecular targets for the diagnosis and/or treatment of luteal insufficiency leading to early pregnancy loss, a significant cause of infertility in livestock and humans. We are currently investigating the potential of circulating RNAs as early-life biomarkers of health and productivity in cattle. We have defined serum-free culture conditions for the propagation of chicken primordial germ cells and determined that their propagation depends on three growth factors. The use of this defined medium for culture of chicken primordial germ cells significantly increases the success of isolating both male and female primordial germ cells (with equal efficiency, which was previously a major roadblock) from chick embryos of many breeds, and reduces the effort involved, resulting in a more efficient process. We have shown when primordial germ cells grown in the defined medium and injected into host embryos which are then hatched and raised to breeding age, that the cultured cells can give rise to functional sperm and eggs. We have developed a sterile surrogate host chicken that can used as a host for transplanted primordial germ cells. This host will have a significant '3R's' impact on the number of animals required to generate the desired lines. This technology forms the basis of a process for conserving the genetics of breeds of chickens. Prior to this development it had not be possible to preserve female gametes, which is an absolute requirement for preservation of breeds in birds. This is because in birds it is the female that is heterogametic (with ZW sex chromosomes) so storage of frozen semen cannot preserve the complete genome of a breed. We have increased our understanding on the control of sexual dimorphism in growth to the expression of genes in the feeding centre of the brain in the hypothalamus. This may explain, at least in part, the differences in growth and feed conversion efficiency between the sexes. Controlling growth in meat type breeding hens and cockerels is one of the major challenges to reproductive success and the industries sustainability. In a collaboration we utilised the CRISPR/Cas9 system to edit the NANOS2 gene in pig embryos to generate offspring with mono-allelic and bi-allelic mutations. We found that NANOS2 knockout pigs phenocopy knockout mice with male-specific germline ablation but other aspects of testicular development are normal. Moreover, male pigs with one intact NANOS2 allele and female knockout pigs are fertile. |
| Exploitation Route | Our greater understanding of the fundamental differences between male and female birds relating to the mechanism of sex determination in birds, will inform approaches to manipulating sex ratios in production chickens. This knowledge will also inform the development of treatments for diseases, for example, due to innate differences in responses of male and female birds. The development of a method for in ovo sexing of chickens may form the basis of a method to sex chickens before hatch. Efficient isolation of primordial germ cells from chickens may form the basis of a method for storing the genetic information of breeds of chickens. With the addition of the observation of differences in the orexigenic genes in the neurones of males and females to that of autosomal loci we are closer to the position of developing a universal hypothesis for the genetic control of growth in chickens. This may help us understand metabolic efficiency during growth which has implications for meat type poultry production especially with regard to controlling the growth of breeders. From an agriculture perspective, NANOS2 knockout male pigs are expected to serve as an ideal surrogate for transplantation of donor spermatogonial stem cells to expand the availability of gametes from genetically desirable sires. |
| Sectors | Agriculture Food and Drink |
| Description | Male meat poultry have a greater food conversion efficiency than female meat birds and are approximately 33% heavier at the time of marketing. A number of commercial enterprises and academic researchers have attempted to increase meat production from female birds by sex-reversing these birds. These efforts have focused on adjusting the hormonal profiles of the birds either by the direct administration of hormones, or by altering the developmental fate of the gonads. To date, these efforts have been unsuccessful. Our findings that the sexual phenotype is cell autonomous should permanently curtail such efforts in endocrine modulation and guide the search for sex determination mechanisms to a focus on intracellular factors. We have completed development of an in-ovo sexing assay to determine the sex of chicks before hatch that fully meets the timing and cost requirements of the poultry industry to remove eggs of the unwanted sex before hatch. This assay can identify the sex of chick embryos from nanolitre volumes of whole blood in under five minutes. The assay is currently being tested by industrial partners under commercial production conditions. If this assay can be successfully applied, this procedure will lead to increases in food production and will address a significant poultry welfare issue, the culling of unwanted chicks (mainly males in egg production lines) post-hatch. We have used the improved culture conditions for chicken primordial germ cells to cryopreserve hundreds of germ cell lines of the inbred chicken lines maintained at the Bumstead facility at RI and are in discussions about applying this technology to storage of rare breeds and commercial chicken breeds. Roslin Technologies is currently commercialising these developments. We also have communicated these results to other research groups including researchers at the NIGL, Japan through a Japan Partnering award and trained visiting researchers from UK, EU and USA in using our technology. We have identified novel biomarkers of reproduction function in livestock. We are now in discussions with commercial partners to develop appropriate diagnostic strategies that would allow the use of these biomarkers on-farm. We have also established links with the IAEA-FAO tropical livestock production programme and academic groups in South America to test the utility of these biomarkers in smallholder farm systems of developing countries. Following from our miRNA biomarker discoveries 1) we are now carrying-out a Pathfinder/ISCF-funded UK-wide market survey on the commercialisation potential of diagnostic miRNAs for cattle and 2) are partners in an ISCF-funded industrial collaboration to explore the potential of existing diagnostic platforms towards the application of miRNAs in cattle diagnostics |
| First Year Of Impact | 2017 |
| Sector | Agriculture, Food and Drink |
| Impact Types | Economic |
| Description | IAIEA-FAO consultancy |
| Geographic Reach | Multiple continents/international |
| Policy Influence Type | Participation in a guidance/advisory committee |
| Description | BBSRC Response mode |
| Amount | £1,000,000 (GBP) |
| Funding ID | BB/N018672/1 |
| Organisation | Biotechnology and Biological Sciences Research Council (BBSRC) |
| Sector | Public |
| Country | United Kingdom |
| Start | 01/2017 |
| End | 04/2020 |
| Description | Case Studentship |
| Amount | £140,000 (GBP) |
| Organisation | Biotechnology and Biological Sciences Research Council (BBSRC) |
| Sector | Public |
| Country | United Kingdom |
| Start | 11/2012 |
| End | 10/2016 |
| Description | Japan Partnering Award |
| Amount | £25,000 (GBP) |
| Organisation | Biotechnology and Biological Sciences Research Council (BBSRC) |
| Sector | Public |
| Country | United Kingdom |
| Start | 03/2014 |
| End | 10/2018 |
| Description | Kurdistan studentship |
| Amount | £70,000 (GBP) |
| Organisation | Iraqi Government |
| Sector | Public |
| Country | Iraq |
| Start | 06/2012 |
| End | 06/2016 |
| Description | SRUC award |
| Amount | £80,000 (GBP) |
| Organisation | Scotland's Rural College |
| Sector | Academic/University |
| Country | United Kingdom |
| Start | 08/2016 |
| End | 03/2017 |
| Description | Sub-award from ISCF Transforming Food Production Seeding Award (ISCF-TFP-SA-Edinburgh). Dr Xavier Donadeu 'Exploring the commercialisation potential or miRNA diagnostics for dairy cattle'. |
| Amount | £6,200 (GBP) |
| Funding ID | ISCF-TFP-SA-Edinburgh |
| Organisation | Biotechnology and Biological Sciences Research Council (BBSRC) |
| Sector | Public |
| Country | United Kingdom |
| Start | 09/2018 |
| End | 02/2019 |
| Description | Sub-award from ISCF Transforming Food Production Seeding Award (ISCF-TFP-SA-Edinburgh). Dr Xavier Donadeu 'Roslin-DestiNA Genomics Ltd collaboration: a microRNA (miRNA) diagnostic platform for early pregnancy diagnosis in dairy cattle'. |
| Amount | £19,250 (GBP) |
| Funding ID | ISCF-TFP-SA-Edinburgh |
| Organisation | Biotechnology and Biological Sciences Research Council (BBSRC) |
| Sector | Public |
| Country | United Kingdom |
| Start | 09/2018 |
| End | 02/2019 |
| Title | Chicken line for investigating sex determination |
| Description | chicken line with edited sex-determining gene |
| Type Of Material | Model of mechanisms or symptoms - non-mammalian in vivo |
| Year Produced | 2018 |
| Provided To Others? | No |
| Impact | N/A |
| Title | Culturing of chicken stem cells for the cryopreservation of chicken breeds |
| Description | We have developed serum free culture conditions for propagating the stem cells that make sperm or eggs in chicken. These stem cells are taken from a chicken embryo and cultured in vitro to increase their numbers. These cells can then be cryopreserved safely and indefinitely. At a later time, the cells are introduced into a surrogate host embryo and the offspring from this host bird will come from the introduced cells. Our culture methods allows us to propagate these cells from any breed of chicken. These cells can be stored in liquid nitrogen and used to establish a frozen biobank for poultry breeds. |
| Type Of Material | Cell line |
| Year Produced | 2015 |
| Provided To Others? | Yes |
| Impact | We have communicated this cell culture technology to many research laboratories with the goal that they would be able to replicate our findings and begin to biobank breeds of chicken using cultured stem cells. These laboratories are in Japan, Israel, UAE, Iran, France, Hungary, USA, Germany. We have worked closely through our Japan Partner Award with Dr Tagami's laboratory in Tsukuba so that his researchers could implement our cell culture methodology. |
| URL | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4682126/ |
| Title | Lines of edited PGCs for investigating germ cell development |
| Description | Lines of edited PGCs for investigating germ cell development |
| Type Of Material | Cell line |
| Year Produced | 2018 |
| Provided To Others? | No |
| Impact | N/A |
| Title | Small RNA biomarkers in livestock |
| Description | Developed procedures for isolation and genome-wide identification of tissue-derived small RNA biomarkers in livestock biofluids. |
| Type Of Material | Technology assay or reagent |
| Year Produced | 2017 |
| Provided To Others? | Yes |
| Impact | Technology to be tested towards improvement of early pregnancy detection in livestock from small holder farms under IAEA-FAO tropical livestock production programme |
| Title | plasma miRNome |
| Description | Have produced comprehensive information on small RNA expression in the plasma of livestock |
| Type Of Material | Database/Collection of data |
| Year Produced | 2016 |
| Provided To Others? | Yes |
| Impact | Unknown |
| Description | CIEL Calf & Youngstock" interest group |
| Organisation | Centre of Innovation Excellence in Livestock |
| Country | United Kingdom |
| Sector | Private |
| PI Contribution | Contribute expertise/interest in early-life biomarkers of lifelong health in cattle |
| Collaborator Contribution | Future opportunities for collaboration with other CIEL members |
| Impact | None yet |
| Start Year | 2018 |
| Description | FAO consultancy |
| Organisation | FAO/IAEA Agriculture and Biotechnology Laboratories |
| Country | Austria |
| Sector | Charity/Non Profit |
| PI Contribution | Participation in IAEA-FAO consultants meeting on "Novel technologies for diagnosis of early pregnancy in cattle" |
| Collaborator Contribution | Organisation of consultants meeting |
| Impact | New protocols were designed for early diagnosis of pregnancy using small RNAs in small holder farms of developing countries. Collaboration will involve an IAEA fellowship for field testing of relevant protocols |
| Start Year | 2017 |
| Description | Pig breeding with Genus |
| Organisation | Genus plc |
| Country | United Kingdom |
| Sector | Private |
| PI Contribution | Developed and demonstrated gene editing in pig zygotes. |
| Collaborator Contribution | Supply of animal resources and funds. |
| Impact | Several publications, presentations at scientific meetings, media opportunities and joint research grants. |
| Start Year | 2010 |
| Description | SRUC collaboration on early life biomarkers in cattle |
| Organisation | Scotland's Rural College |
| Country | United Kingdom |
| Sector | Academic/University |
| PI Contribution | Provided expertise on small RNA analysis in livestock and laboratory facilities for the study |
| Collaborator Contribution | Provided funding, animal samples, and expertise in cattle genetics |
| Impact | Manuscript just submitted to Scientific Reports, Responsive mode BBSRC application in preparation |
| Start Year | 2016 |
| Description | avian gonadal development |
| Organisation | Guangxi University |
| Country | China |
| Sector | Academic/University |
| PI Contribution | discussions and laboratory work |
| Collaborator Contribution | discussions and laboratory work |
| Impact | publications |
| Start Year | 2014 |
| Description | mirna biomarkers of reproductive status in cattle |
| Organisation | Zoetis |
| Country | United States |
| Sector | Private |
| PI Contribution | Performed studies which resulted in the identification of miRNA biomarkers of reproductive status in cattle |
| Collaborator Contribution | Provided funding |
| Impact | A miRNA target network putatively involved in follicular atresia. Donadeu FX, Mohammed BT, Ioannidis J. Domest Anim Endocrinol. 2017 Jan;58:76-83. doi: 10.1016/j.domaniend.2016.08.002. Circulating microRNA Profiles during the Bovine Oestrous Cycle. Ioannidis J, Donadeu FX. PLoS One. 2016 Jun 24;11(6):e0158160. doi: 10.1371/journal.pone.0158160. PMID: 27340826 Circulating miRNA signatures of early pregnancy in cattle. Ioannidis J, Donadeu FX. BMC Genomics. 2016 Mar 3;17:184. doi: 10.1186/s12864-016-2529-1. PMID: 26939708 MicroRNA indicators of follicular steroidogenesis. Donadeu FX, Sontakke SD, Ioannidis J. Reprod Fertil Dev. 2016 Feb 11. doi: 10.1071/RD15282. |
| Start Year | 2012 |
| Description | sex determination in birds |
| Organisation | Francis Crick Institute |
| Country | United Kingdom |
| Sector | Academic/University |
| PI Contribution | discussions, laboratory work, funding applications |
| Collaborator Contribution | discussions, laboratory work, funding applications |
| Impact | publications |
| Start Year | 2012 |
| Title | Use of transgenic techniques to manipulate sex ratio or progeny |
| Description | Using genetic engineering to alter sex ration of offspring in farm breeding |
| IP Reference | US61/971,869 |
| Protection | Patent application published |
| Year Protection Granted | 2014 |
| Licensed | Commercial In Confidence |
| Impact | research funds |
| Description | Cell autonomous sex identity |
| Form Of Engagement Activity | A press release, press conference or response to a media enquiry/interview |
| Part Of Official Scheme? | No |
| Geographic Reach | International |
| Primary Audience | Public/other audiences |
| Results and Impact | Favourable feedback none |
| Year(s) Of Engagement Activity | 2010 |
| Description | Contributed to online article |
| Form Of Engagement Activity | A magazine, newsletter or online publication |
| Part Of Official Scheme? | No |
| Geographic Reach | International |
| Primary Audience | Public/other audiences |
| Results and Impact | Contributed to an article on BBC Earth |
| Year(s) Of Engagement Activity | 2015,2016 |
| URL | http://www.bbc.com/earth/uk |
| Description | Institute open day |
| Form Of Engagement Activity | Participation in an open day or visit at my research institution |
| Part Of Official Scheme? | No |
| Geographic Reach | Regional |
| Primary Audience | Public/other audiences |
| Results and Impact | discussion with members of public none |
| Year(s) Of Engagement Activity | 2012,2013,2014 |
| Description | Meet the cow |
| Form Of Engagement Activity | Participation in an open day or visit at my research institution |
| Part Of Official Scheme? | No |
| Geographic Reach | Local |
| Primary Audience | Public/other audiences |
| Results and Impact | Presentation of research work to a small group |
| Year(s) Of Engagement Activity | 2016 |
| Description | Meet the cows |
| Form Of Engagement Activity | Participation in an open day or visit at my research institution |
| Part Of Official Scheme? | No |
| Geographic Reach | Local |
| Primary Audience | Public/other audiences |
| Results and Impact | Presentation of scientific work to families visiting University of Edinburgh experimental dairy cow at Langhill |
| Year(s) Of Engagement Activity | 2016 |
| Description | Midlorthian Science Festival Debate |
| Form Of Engagement Activity | A talk or presentation |
| Part Of Official Scheme? | Yes |
| Geographic Reach | Local |
| Primary Audience | Public/other audiences |
| Results and Impact | Constructive and lengthy debate Invited back to next festival |
| Year(s) Of Engagement Activity | 2014 |
| Description | Published article received press coverage |
| Form Of Engagement Activity | A magazine, newsletter or online publication |
| Part Of Official Scheme? | No |
| Geographic Reach | International |
| Primary Audience | Public/other audiences |
| Results and Impact | Published article discussed in public online forum |
| Year(s) Of Engagement Activity | 2017 |
| URL | http://www.bbc.co.uk/news/uk-scotland-edinburgh-east-fife-39006713 |
| Description | Published article receiving press coverage |
| Form Of Engagement Activity | A magazine, newsletter or online publication |
| Part Of Official Scheme? | No |
| Geographic Reach | International |
| Primary Audience | Public/other audiences |
| Results and Impact | Press article on gene targeted chicken used to study germ cell development and to develop surrogate host chickens for rare breed conservation |
| Year(s) Of Engagement Activity | 2017 |
| URL | https://www.ft.com/content/10000b26-f52c-11e6-8758-6876151821a6 |
| Description | contributed to online article |
| Form Of Engagement Activity | A magazine, newsletter or online publication |
| Part Of Official Scheme? | No |
| Geographic Reach | International |
| Primary Audience | Public/other audiences |
| Results and Impact | Contributed to article in The Natural History magazine |
| Year(s) Of Engagement Activity | 2017 |
| URL | http://www.naturalhistorymag.com/ |