There are many unknown facts and reasons behind male infertility. However, science is taking rapid strides in this field and the successful sequencing of the entire genome of individual sperm may prove to be a milestone in understanding male fertility.
In an important scientific breakthrough, scientists from Stanford University have been successful in determining the entire genome sequence of 91 human sperms of a single 40 years old man. His whole genome sequence (obtained from diploid cells) had already been studied previously. Comparing the genome sequence of the sperm with that obtained from the diploid cell provides a wonderful insight about the naturally occurring genetic variations in a single individual.
Almost all the cells of the human body contain a pair of 23 chromosomes and are therefore referred to as diploid cells. During the formation of sperms or eggs (male and female gametes respectively), a process of cell division, called as meiosis, takes place and as a result, the sperm or the egg contains only a single set of 23 chromosomes. They are therefore called as haploid cells. The fertilized embryo, formed as a result of the fusion of the sperm and egg, again contains a pair of 23 chromosomes.
During meiosis, a natural process called as recombination takes place which ensures that the embryo formed after fertilization contains a healthy blend of genes from all the four grandparents. During recombination, parts of the chromosome get shuffled and hence, the genetic sequence of each sperm varies slightly. Sibling variation can be attributed to the process of recombination.
The team of researchers, led by Stephen Quake from the Stanford School of Medicine’s Department of Bioengineering, was able to find out the entire genomic sequence of 91 sperms. They could analyze all the sites, from the possible 1.2 million positions in the DNA, where recombination took place. Apart from the “recombination hotspots” where re-combinations commonly take place, they were also able to find out that chromosomes in certain sperms recombined at totally unexpected places. The process of recombination, leading to genetic reshuffling, is unique to each sperm cell and leads to increased genetic diversity in children of the same parent. The researchers found 23 re-combinations in the sampled sperm, along with 25 to 36 new mutations. The mutations varied from small to as big as missing of a full chromosome. Such mutations can render a sperm incapable of fertilizing an egg and be an important cause behind male infertility.
The researchers feel that future research into the genomic sequencing of a sperm can help us to understand many other causes that may be leading to male infertility. The results of the present study have been published in the July 19 online issue of the journal ‘Cell.’
The team of researchers, led by Stephen Quake from the Stanford School of Medicine’s Department of Bioengineering, was able to find out the entire genomic sequence of 91 sperms. They could analyze all the sites, from the possible 1.2 million positions in the DNA, where recombination took place. Apart from the “recombination hotspots” where re-combinations commonly take place, they were also able to find out that chromosomes in certain sperms recombined at totally unexpected places. The process of recombination, leading to genetic reshuffling, is unique to each sperm cell and leads to increased genetic diversity in children of the same parent. The researchers found 23 re-combinations in the sampled sperm, along with 25 to 36 new mutations. The mutations varied from small to as big as missing of a full chromosome. Such mutations can render a sperm incapable of fertilizing an egg and be an important cause behind male infertility.
The researchers feel that future research into the genomic sequencing of a sperm can help us to understand many other causes that may be leading to male infertility. The results of the present study have been published in the July 19 online issue of the journal ‘Cell.’
There Are Many Forms Of Male Infertility That Are Yet To Be Identified
For their experiment, Quake and his team used a microfluidic chip, which was about 3 centimeters small and had multiple channels and valves. A small sample of the man’s ejaculate was injected into the channels of the microchip. The 91 sperm cells present in the sample ejaculate were separated into individual chambers with the help of valves. The genes in each sperm cell were amplified so that they could be sequenced.
The high density genotyping of the genomes of each of the 91 sperm cells was used to create a personal recombination map. It was compared with the original pedigree data, derived by the sequencing of the man’s diploid cell, under high resolution to reveal significant differences. 31 of the sperm cells were subjected to high throughput sequencing in order to measure the frequency of large scale instability of the genomes. Further deeper sequencing of eight of the sperm cells brought out the de novo mutation rates.
According to the experts, the mutation rates are higher and different in sperm cells of men suffering from infertility compared to men with normal fertility rates. There are many forms of male infertility that are yet to be identified. Once we are able to fully comprehend the exact implications of these mutations, we will be able to understand the reasons behind many other causes of male infertility. It will also help us to understand the effect of ageing on the quality of sperm cells and male fertility. Similarly, we will be able to understand the role of recombination in male infertility.
The sequencing technique employed in the present experiment destroyed the sperm matter, rendering the sperm useless for fertilization. However, the experts feel that if they are able to capture and screen a sperm cell just before it divides by way of meiosis, they would be able to sequence one and get to know about the genetic sequence of the other one, without destroying its matter. This may even lead to choosing a healthy sperm before fertilization in order to produce a healthy child.
The researchers hope that a similar technique could be applied to select eggs for in vitro fertilization. Every time an egg cell is produced, three other non-functional cells are produced alongside. Although these cells do not take part in fertilization, yet they are important as they contain the same genetic material as the egg cell. Analyzing the genome of these cells and screening it for the presence of any genetic disease can help in better selection of egg cells for IVF.
Sequencing of genomes can also play an important role in our understanding of various cancers and help us to formulate specific treatment for them. This can be achieved by genomic sequencing of a single cell of a particular tumor for various mutations and re-combinations. Targeted therapy for these mutations can be the future of cancer treatment.
Although nobody is denying the tremendous scope of genome sequencing, there are certain legal loopholes as well. Dr. Don Conrad, a human geneticist at Washington University School of Medicine in Saint Louis, has pointed out that if during genome sequencing, one were to discover a mutation that puts a person under high risk for developing certain cancer, is the doctor obligated to tell the patient about this? Likewise, are the scientists involved in genome sequencing, under compulsion to look for certain mutations? It is necessary to debate all the ethical issues related to the process of genome sequencing at length before making the technique ready for commercial use.
The sequencing technique employed in the present experiment destroyed the sperm matter, rendering the sperm useless for fertilization. However, the experts feel that if they are able to capture and screen a sperm cell just before it divides by way of meiosis, they would be able to sequence one and get to know about the genetic sequence of the other one, without destroying its matter. This may even lead to choosing a healthy sperm before fertilization in order to produce a healthy child.
The researchers hope that a similar technique could be applied to select eggs for in vitro fertilization. Every time an egg cell is produced, three other non-functional cells are produced alongside. Although these cells do not take part in fertilization, yet they are important as they contain the same genetic material as the egg cell. Analyzing the genome of these cells and screening it for the presence of any genetic disease can help in better selection of egg cells for IVF.
Sequencing of genomes can also play an important role in our understanding of various cancers and help us to formulate specific treatment for them. This can be achieved by genomic sequencing of a single cell of a particular tumor for various mutations and re-combinations. Targeted therapy for these mutations can be the future of cancer treatment.
Although nobody is denying the tremendous scope of genome sequencing, there are certain legal loopholes as well. Dr. Don Conrad, a human geneticist at Washington University School of Medicine in Saint Louis, has pointed out that if during genome sequencing, one were to discover a mutation that puts a person under high risk for developing certain cancer, is the doctor obligated to tell the patient about this? Likewise, are the scientists involved in genome sequencing, under compulsion to look for certain mutations? It is necessary to debate all the ethical issues related to the process of genome sequencing at length before making the technique ready for commercial use.
- “Genome-wide Single-Cell Analysis of Recombination Activity and De Novo Mutation Rates in Human Sperm”, by Stephen R. Quake et al, published in the July 20, 2012 issue of the journal Cell, accessed on August 19, 2012.
- “Sperm sequencing could help fight infertility”, by Jessica Hamzelou, published in the July 19, 2012 issue of the NewScientist, accessed on August 19, 2012.
- “Sequencing of Single Sperm Could Reveal New Infertility Causes”, by Katherine Harmon, published on July 19, 2012 at scientificamerican.com, accessed on August 19, 2012.
- Photo courtesy of ntr23/183605132 on Flickr: www.flickr.com/photos/ntr23/183605132/
- Photo courtesy of mwhitehead on Flickr: www.flickr.com/photos/mwhitehead/6014802154/