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We have a collaboration with the lab of Prof. Lawrence Smith, on studying the genome of horse clones! Very exciting project that Pamela explained this morning at lab meeting – and this awesome horse picture she displayed. As soon as the data is available (hard disk issues…), we will tell you more about it.

In the meantime, do you know the details of cloning Dolly, the world’s most famous sheep? She was born from three mothers and created using the technique of somatic cell nuclear transfer. The first mother provided the DNA, the second the egg and the last the uterus. In this technique, the nucleus of the egg cell is removed and replaced by one of a somatic cell from the animal to be cloned. After stimulation (with a shock), the reprogrammed egg will begin to divide. From there, there are two avenues : therapeutic cloning, where stem cells can be obtained from the clone embryo, or reproductive cloning, where the clone embryo is implanted into a host mother until birth.

High neonatal death make the process of reproductive cloning difficult, and the reasons for this remain unknown. Also, in non-human species, imprinting disorders in cloned offspring are observed, possibly linked to the absence of meiosis-specific mechanisms, or simply absence of a sperm cell. In fact, somatic cell nuclear transfer can also be done using a sperm cell, along with a fertilized egg nucleus and an enucleated egg cell, leading to a child with three biological parents. All three parents contribute genetically: dad and mom #1 contribute nuclear DNA, and mom #2 contributes mitochondrial DNA. This is called mitochondrial replacement therapy. It can be used to allow women with severe mitochondrial diseases to have disease-free children, but it still poses many ethicals, social and legal concerns. Furthermore, coordinated mitochondrial-nuclear interactions may have become highly specific over evolutionary time, so are they likely to be a problem?

Further reading

Smith et al. Benefits and problems with cloning animals. Can Vet J. 2000; 41(12): 919–924

Rideout III et al. Nuclear Cloning and Epigenetic Reprogramming of the Genome. Science. 2001; 293(5532): 1093-1098

Reinhardt et al. Mitochondrial Replacement, Evolution, and the Clinic. Science. 2013; 341 (6152): 1345-6

Here is a picture from Isabel’s slide this week, from her project on the pharmacogene ADCY9, from a collaboration with Marie-Pierre Dubé’s and Jean-Claude Tardif’s teams.

Genome-wide association studies have revealed associations between polymorphisms in ADCY9 and response to the drug dalcetrapib, an inhibitor of the CETP protein which increases the serum levels of HDL-C. Other SNPs within ADCY9 have been associated with various phenotypes such as asthma, obesity and malaria. It seems like a good candidate for pleiotropy!

In Isabel’s project, pharmacogenomics meets population genetics meets transcriptomics! We are excited about the results and Peruvians are standing out!

This is a series of volcano plots (that actually look more like “whale tail” plots) made by Axel, our computer science teacher turned bioinformatics intern, for his transcriptomics project, a collaboration with Dr. Jocelyn Dupuis at the Montreal Heart Institute and the company Prometic Life Sciences. We work on pulmonary hypertension associated with left heart disease in a rat model and are exploring biological mechanisms and effects of novel treatments.

Today, Léo presented on the mathematical principles behind a Principal Component Analysis (PCA). It was a great refresher for myself, and amazing to give students a clear picture of what this technique does and why we use it so much for dimensionality reduction. Also, Léo prompted a discussion about why variance and variability are so important in understanding the world with these images of Mona Lisa (La Joconde), one of which is Mona Lisa with her Cat (its name is Zarathustra). I loved it! He explained that in terms of information theory,  variation is where the information resides. Information comes from comparison (of the two paintings), and this information is what makes the “message” important (there is a cat in Mona Lisa’s arms). This whole discussion about variance, comparison and variability is really in line with the major aim of the entire field of population genetics (my field !!), a field “that deals with genetic differences within and between populations, and is a part of evolutionary biology “, as formulated by Wikipedia. This is probably one reason why PCA is so widely used in analysis of biological data. Also, please note that deep learning methods can generate tons of art work with cats!

The featured picture from last week lab meeting is a figure from Justin’s presentation, made by Isabel. First, I like it because I am happy to see that trainees are collaborating! Second, it combines recombination hotspots with Cytochrome P450 (CYP) genes. It shows the fine-scale recombination rates, from genetic maps computed in different human populations from the 1000 Genomes data, in the CYP4F gene cluster.

Recombination is the process by which every child receives a unique mosaic of parental chromosomes. In most species, recombination occurs in narrow genomic segments, called recombination hotspots. My research until recently was mainly dedicated to the study of recombination hotspots, and the fascinating gene PRDM9, which I like to say is my favorite gene in the entire genome. It evolves very rapidly under strong positive selection, is implicated in disease, is critical for fertility. More recently, however, I have had another favorite gene family, the CYP genes. CYP enzymes are able to catalyze a considerable variety of oxidations for many structural classes of chemicals (including the majority of drugs), in all forms of life (bacteria, fungi, plants, birds, insect, reptiles and mammals). Similarly to PRDM9, they evolve quickly : these genes exhibit an exceptionally high number of mutations. Striking inter-individual and geographic differences in CYP allele frequencies are found in humans. The main hypothesis is that their evolution has first been influenced by interactions between animals and plants, and second, by diet and environmental pollutants impacting humans over thousands of years and differing between ethnic groups.

I am now fascinated by the evolution of these CYP families, but, by professional bias, let’s start by looking at the recombination landscape!

 

Further reading

Alves I, Houle AA, Hussin JG, Awadalla P. The impact of recombination on human mutation load and disease. Philos Trans R Soc Lond B Biol Sci. 2017 Dec 19;372(1736).

Paigen, K and Petkov P. PRDM9 and Its Role in Genetic Recombination. Trends in Genetics, 2018. 34(4): p.291-300.

Gonzalez, F.J. and D.W. Nebert, Evolution of the P450 gene superfamily: animal-plant ‘warfare’, molecular drive and human genetic differences in drug oxidation. Trends Genet, 1990. 6(6): p.182-6.

Nebert, D.W., Polymorphisms in drug-metabolizing enzymes: what is their clinical relevance and why do they exist? Am J Hum Genet, 1997. 60(2): p.265-71.

This week we had our first official OMICS group meeting : there was 12 of us around the table! After each group meeting, I will choose a picture I liked from the presenters’ slides and post it here. This week, it is a slide from Léo! He made a suberb PCA plot, that looks like a fly! Who can guess which dataset this is ?

I will collect here images and ideas that come from my trainees.