Human sperms' DNA is no longer a secret. Scientists have sequenced the full genomes of 91 male sex cells.
The cells were taken from a healthy, 40-year-old man and analyzed using a new high-throughput, microfluidic sequencing system. The team identified the genetic diversity established in the individual’s sex cells by comparing the genomes of the individual sperm
"The breakthrough here is the technology. It gives us the ability to look at the sequence of an individual sex cell and is a window into the sequences, genes, or rates of mutations that a man can contribute to his offspring," said study Barry Behr, director of Stanford's in vitro fertilization laboratory and a co-author of the new study.
He said that if the technology continues to develop over the next five to 10 years, it will allow scientists and physicians to look at the sex cells of a particular individual and diagnose or detect potential reproductive problems.
To study the male sex cells, the team first isolated and sequenced nearly 100 sperm from the healthy, 40-year-old male subject. His whole genome, generated from non-sex cells, had already been sequenced to a high level of accuracy. Comparing the non-sex cell genome with the sperm sequences, the team tracked where mutations and recombination in the DNA occurred.
Recombination is a natural process that drives genetic variation and also ensures that sexually reproducing organisms don't spread dangerous mutations to every subsequent generation of offspring. In the past, scientists had to use genetic studies of populations to estimate how often DNA recombinations and mutations occurred. The new study takes those observations from the population level to the individual cell level, an increase in resolution that goes from looking at "paragraphs in a book to letters in a word," said Behr.
He explained that it has taken his colleague, Stanford bioengineer Stephen Quake and his lab, nearly a decade to develop the technology to sequence a single sperm cell. It took so long because of the distinct features of the male sex cell. A sperm is not like a normal cell in the body. It is small, about a hundredth the width of a grain of salt. The cell itself has a nucleus of DNA that is wound six times tighter than the genetic material in an average cell and has different proteins operating it. And, because sperm is a sex cell, it has only one set of 23 chromosomes, rather than two, meaning less material to sequence.
Despite the challenges, the team finally succeeded in sequencing the sperm. The scientists found that each male sex cell experienced about 23 recombination events. The events did not all occur in the same region of the genome. The individual sperm also showed variability in the number and severity of spontaneously arising genetic mutations. Two sperm, for example, were missing entire chromosomes.
The observations show how genetic variation arises at a DNA level and closely match previously reported population data (2) about recombination and mutation rates in sex cells.
As scientists begin to study different men's sperm sequences, they will be able to measure what factors – such as diet, exercise, and age – influence mutation rates in the cells and how that affects reproduction, said Behr. With that knowledge, physicians could then better diagnose reproductive problems in men and possibly improve the odds of success for in vitro fertilization.
Behr added that he would like to sequence individual human egg cells next, but they aren’t as readily available as sperm, so the challenge will be even greater.
1. Wang, J. et al. (2012). Genome-wide Single-Cell Analysis of Recombination Activity and De Novo Mutation Rates in Human Sperm. Cell 150, 402–412.
2. Kong, A. et al. (2010). Fine-scale recombination rate differences between sexes, populations and individuals. Nature 467, 1099–1103.