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Male Infertility Diagnosis to Benefit from Single Sperm Test

Tim Boyer's picture

Researchers have recently announced that they are the first to sequence the entire genome of a single sperm cell and compare it to the genetic sequence of the entire genome of the owner of the sperm. The benefit of this research is that it can help men experiencing male infertility to receive a diagnosis that is based not just on the overall physical health of his sperm, but more precisely, on the genetic health of his sperm as well.

Two genetic events make us the unique individuals we are: recombination and mutation.

Meiotic recombination is a “mixing” event that occurs in early germ cells destined to become sperm or eggs. Just like normal body cells such as the cells found in organs like the heart, liver, skin, etc., the early germ cells possess two copies of each of the cell's 23 chromosomes. The two copies of genetic material are referred to as diploid cells. To prevent the development of an embryo with more than a diploid number of chromosomes, each sperm and egg must split its DNA complement in half to its haploid number, so that a child will inherit one-half of its diploid DNA from each parent. Prior to the chromosomal division, the paired chromosomes in early germ cells join briefly at their centers and exchange both bits and large sections of their DNA—a process called recombination. The reason for this is that it ensures each germ cell contains a complement of chromosomes that are variably unique from the parent.

A second genetic event that occurs in sperm and egg cells is chance mutation that offers a second way to provide genetic variability between parent and child. For the most part, these mutations are slight and usually non-lethal. In worst case scenarios, the mutation(s) can occur in an important region of DNA and result in a child born with a genetic condition.

In a recent study published in the journal Cell, researchers have announced that they have successfully sequenced not only the entire diploid genome of an individual, but the entire haploid genome from a single sperm from the same individual. This in turn allowed the researchers the opportunity to compare the two genomes to see how much variation occurred between the individual’s genomic DNA that he inherited from his parents, to the DNA in his sperm that he could pass onto his children.

According to a press release issued by Stanford University Medical Center, "Single-sperm sequencing will allow us to chart and understand how recombination differs between individuals at the finest scales. This is an important proof of principle that will allow us to study both fundamental dynamics of recombination in humans and whether it is involved in issues relating to male infertility," said Gilean McVean, PhD, professor of statistical genetics at the Wellcome Trust Centre for Human Genetics.

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The actual study consisted of isolating and sequencing approximately 100 sperm from a 40-year-old male with normal appearing semen and the father of healthy children. His genomic DNA was also isolated, sequenced and compared to each of the single sperm DNA.

What the researchers found was that they could determine where the genetic recombination had occurred in the DNA of his early germ cells and how often new mutations arose in the DNA—the two aforementioned genetic events that causes variability between parents and their offspring. They also identified 25 to 36 new mutations at the single-letter level of the DNA code in each of the sperm cells. The DNA code is comprised of the genetic letters A, G, C and T.

"For the first time, we were able to generate an individual recombination map and mutation rate for each of several sperm from one person," said study co-author Barry Behr, PhD, HCLD, professor of obstetrics and gynecology and director of Stanford's in vitro fertilization laboratory. "Now we can look at a particular individual, make some calls about what they would likely contribute genetically to an embryo and perhaps even diagnose or detect potential problems."

One of those potential problems is male infertility. Up to now, a diagnosis of male infertility was based on the overall health of a semen sample looking at the concentration of sperm and how well the sperm are able to swim. However, their discovery opens the door toward addressing the genetic health of sperm by noting for example whether someone has an unusually high mutation rate in their sperm or loss of chromosomal material that results in infertility.

"This could serve as a new kind of early detection system for men who may have reproductive problems," said Behr, who also co-directs Stanford's reproductive endocrinology and infertility program. "It's also possible that we could one day use other, correlating features to harmlessly identify healthy sperm for use in IVF. In the end, the DNA is the raw material that ultimately defines a sperm's potential. If we can learn more about this process, we can better understand human fertility."

Two immediate benefits include genetic analysis of sperm that can aid physicians in making an accurate fertility diagnosis so that a couple will know what options are available rather than going through multiple and expensive reproduction therapies that have a poor chance of success. A second benefit is that the single sperm test could also increase our understanding of male aging and how it affects sperm health.

Image Source: Courtesy of Wikipedia

Reference: “Genome-wide Single-Cell Analysis of Recombination Activity and De Novo Mutation Rates in Human Sperm” Cell Vol. 150 issue 2, 20 July 2012, Pages 402–412; Jianbin Wang, H. Christina Fan, Barry Behr and Stephen R. Quake