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First-Ever Gene Sequencing of Sperm May Help with Infertility

a blog by Claire, July 20, 2012

For the first time, scientists have sequenced the entire genome of a sperm, which could lead to a new understanding of male fertility.

Whole genome sequencing is a laboratory process that determines the complete DNA (the genetic instructions) sequence of an organism's genome (hereditary information). This is the first study, to report the whole-genome sequence of a human gamete (egg or sperm), which are the cells that become a child and pass on physical traits. The study is published in the July 20 issue Cell.

With sperm cells, there is a natural process called recombination, which is the the process in which genetic material is broken and joined to other genetic material. This process is what ensures that a baby is a blend of DNA from all four of his or her grandparents. Until now, scientists had to rely on genetic studies of populations to estimate how frequently recombination had occurred in individual sperm and egg cells, and how much genetic mixing that entailed.

Now, single-sperm sequencing will allow researchers to understand how recombination differs between individuals, and they will be able to study recombination in humans to see whether it is involved in male fertility issues. The study showed that the previous, population-based estimates had been fairly accurate. On average, the sperm in the sample had each undergone about 23 recombinations (mixing events). However, individual sperm varied greatly in the degree of genetic mixing and in the number and severity of spontaneously arising genetic mutations. For example, two sperm were missing entire chromosomes.

"For the first time, we were able to generate an individual recombination map and mutation rate for each of several sperm from one person," says study co-author Barry Behr, PhD, HCLD, Stanford professor of obstetrics and gynecology and lab director at Stanford Fertility and Reproductive Medicine Center. "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."

Most cells in the human body have 46 chromosomes — two copies of each of 23 chromosomes — and are called "diploid" cells. Sperm and eggs each have one set of 23 chromosomes and are called "haploid" cells. The recombination occurs during a process called meiosis, which partitions a single copy of each chromosome into a sperm (in a man) or egg (in a woman) cell. When a sperm and an egg join, the resulting embryo again has a full complement of DNA.

To ensure an orderly distribution during recombination, pairs of chromosomes are lined up in tight formation along the midsection of the cell. Portions of matching chromosomes are sometimes randomly swapped, which generates much more genetic variation in a potential offspring than would be possible if only intact chromosomes were segregated into the reproductive cells. This genetic mixing process is unique for each sperm cell and egg cell, and problems with this recombination process can generate sperm that are missing portions of chromosomes or whole chromosomes, which makes them incapable or unlikely to fertilization an egg.

The study subject for the Stanford researchers was a 40-year-old man who has healthy offspring. His semen sample appeared normal. The researchers had his whole-genome sequence, which was obtained from diploid cells. They then compared the sequence of the sperm with that of the study subject's diploid genome. They could see, by comparing the sequences of the chromosomes in the diploid cells with those in the haploid sperm cells, where each recombination event took place. They were also able to identify 25 to 36 new single nucleotide mutations in each sperm cell that were not present in the subject's diploid genome. Such random mutations are another way to generate genetic variation, but if they occur at particular points in the genome they can have negative effects.

The geneome sequencing process cannot be used to select sperm for fertilization of eggs during the in vitro fertilization process, because the genome sequencing process destroys the sperm. However, the process could potentially be used to diagnose male infertility and help couples assess their options and help researchers learn more about the changes in sperm quality as a man increases in age.

"This could serve as a new kind of early detection system for men who may have reproductive problems,"Behr says. "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."

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