Infertility and the genetics of sperm

Infertility is becoming increasingly more common with recent estimates of 15-20% of couples experiencing infertility some time in their reproductive life.

A typical fertile couple in their mid-to-late 20s, having regular sex, have about a 20-25% chance of conceiving each month. After 6 months at least 3/4 of such couples will be pregnant, and after a year at least 90%.  For many people the chance of conception may be lower than normal, but for some people infertility is absolute (there may be no sperm, or the woman’s fallopian tubes may be blocked).

About 25% of infertility is calculated to be directly due to the male partner, and another 15-25% probably also has a male contribution.

The diagnosis of male infertility is usually performed by the observation of sperm under the microscope.  Estimates of how many sperm are being produced and their ability to fertilise eggs can be made. However, normal quality semen does not guarantee adequate fertility. The large number of cases of unexplained infertility suggest that abnormal sperm function may be due to genetics.

A recent study has identified a gene expression fingerprint linked with very low pregnancy rates in semen donors with normal semen quality. The researchers analysed semen samples from 68 young and healthy donors whose fertility wasn’t known by looking at the expression profile of 85 genes.

They found significant differences in the expression of individual genes among the eight samples with high and low pregnancy rates.  Combining the results of four of these genes gave a much higher sensitivity to recognize subfertile individuals than with the classical analysis of semen (82% vs. 23%).

The results of this study “opens the door to…understanding the causes of infertility of unknown origin and development, in the future, of an additional test to identify individuals of low fertility despite having normal semen values.”

An aside to this: Don’t believe sperm actually swim?  I didn’t till I saw them down a microscope so here’s a short clip to show you what they look like

Quick fact: the number of sperm in an ejaculate ranges from 20-400 million per ml.

For more information please see the original article.  Images: sperm, egg/sperm.

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Making what’s old new again…

Imagine if you could take something old and make it new again?

That’s exactly what scientists have done by taking skin tissue from heart attack patients and making fresh, beating heart cells. This avoids the risk of cells being rejected by the immune system once they are transplanted.

The idea was first demonstrated in 2007, when scientists identified “pluripotency” genes that could make differentiated cells capable of being other types of cells (explained further in the diagram to the left).

These ‘pluripotency’ genes were identified as being particularly important in embryonic stem cells and are now essential for the production of “induced pluripotent stem cells or iPS cells”.

In this recent study, researchers took skin cells from two men who had survived heart attacks, and reprogrammed them by infecting them with a virus that carried three of the pluripotency genes.

The scientists then grew these and added factors to turn them into fresh heart muscle.  Interestingly, when the iPS cells were injected into rat hearts, they were incorporated into the organ and worked alongside the muscle cells already there.

“This technology needs to be refined before it can be used for the treatment of patients with heart failure, but these findings are encouraging and take us a step closer to our goal of identifying an effective means of repairing the heart and limiting the consequences of heart failure,” says a cardiologist.

When the first iPS cells were reported they were hailed as the next big thing for medicine, but there has always been a concern with how the cells are reprogrammed.  The 2-4 genes that are required for reprogramming are often introduced via viruses but other methods are being developed.

Making enough cells quickly enough for treatment will be another hurdle.  In the latest study it took two weeks to make heart cells from skin tissue, and researchers injected a few million cells, but a heart attack kills off around one billion muscle cells.

This recent work has improved scientists’ understanding of how induced pluripotent stem cells might be used to treat humans with heart disease.

The technique must overcome major hurdles before doctors can begin clinical trials, but the latest work has boosted confidence that it has potential to help patients. Further experiments to investigate whether the procedure is safe and effective are expected to take up to 10 years, so don’t count on your own cells to save your life.

Sources: The Guardian,  body image, cells, and cartoon

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What colour are your eyes?

Blue? Hazel? Brown? Green? Amber? What colour are your eyes?

Eye color is determined by two factors: the pigmentation of the iris (a circular structure responsible for controlling the size of the pupil) and the scattering of light through the fluid of the stroma (fibers and cells that radiate towards the pupil, forming a delicate mesh in which the vessels and nerves are contained) of the iris.

In humans, the pigmentation of the iris varies from light brown to black, depending on the concentration of melanin and the density of the stroma.  Blue, green, and hazel eyes results from the scattering of light in the stroma. Interestingly, neither blue nor green pigments are ever present in the human iris and eye colour varies depending on the lighting conditions.

Eye color is usually thought of as a simple trait but recent research and observation has indicated that eye color does not follow the classical paths of inheritance and the once-held view that blue eye color is recessive has been shown to be incorrect.

There are about 16 different genes responsible for eye color, but it’s mostly attributed to two adjacent genes on chromosome 15, HERC2 and OCA2.

Eye color is influenced by other genetic factors including epistasis (where the effects of one gene are modified by one or several other modifier genes) and incomplete dominance (where the phenotype of the heterozygous genotype is an intermediate of the phenotypes of the homozygous genotypes).

I’ve always thought Kate Bosworth has the most beautiful eyes.  They are different colours due to something called Heterochromia, the excess, or lack of melanin within an iris or part of an iris.

David Bowie also has the appearance of different eye colors due to an injury that caused one pupil to be permanently dilated.

Albinism of the eye also occurs when there is a complete lack of pigmentation and eyes appear red or purple due to the red of retina being visible through the iris.

Today, we don’t have to be stuck with the eye colour we’re born with as you can buy contact lenses of almost every colour imaginable.  What colour eyes would you have if you could choose?

Images: Kate, David Bowie, eyes,

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What’s up with Puberty?

Pimples?  Weird Hair?  Body parts growing?

I’m talking about Puberty, an embarrassing but important developmental stage where we become capable of reproducing.  People start puberty at different ages as the timing is influenced by both genetic and environmental factors.

Studies have suggested that 50–80% of the variation in puberty timing is due to genetic factors.  These are likely due to multiple gene influences and interactions between the genes and environmental factors.

To figure out the genetics behind puberty rare disorders of puberty have been investigated.  These studies identified the hypothalamic-pituitary-gonadal (HPG) axis as being super important.  This axis controls development, reproduction, and aging in animals by producing important hormones such as gonadotropin-releasing hormone (GnRH), luteinizing hormone (LH), and follicle-stimulating hormone (FSH).  Interestingly the HPG axis has important roles during the prenatal, infant, and prepubertal stages of life too.

Other approaches to finding genes underlying complex traits in humans include:

(1) Sequencing of candidate genes by selecting these genes and determining if sequence variants can explain the phenotypic variation.

(2) Genome-wide linkage analyses which uses an unbiased genome-wide scan to identify genes that regulate a specific trait.

(3) Association studies which assess the frequency of a genetic variant in an affected population versus a control population.

Other interesting things I found out;

– Synthetic and naturally occurring substances can alter normal reproductive development by disrupting hormone signaling.

– It’s the gonads (testes and ovaries) that produce the commonly known estrogen and testosterone hormones.

Sources: Cartoon , Picture.

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The Genetics of Skin Cancer

Long gone are the days of slapping on some oil and lying in the summer sun all day. We’re now told to ‘slip, slop, slap, and wrap’ as NZ has one of the highest rates of skin cancer in the world.

Skin cancer, or Melanoma, is cancer of the melanocytes, the cells which are responsible for the colour of our skin.  These cells are most commonly found in our skin but are also found in other parts of the body including the eye.

We now know that getting sunburnt regularly greatly increases your odds of skin cancer but genetics are also thought to play a role.

Recently, the genetics of melanoma has been investigated by comparing the genomes of tumour and normal cells from 25 patients with melanoma. They found that one gene, PREX2, was mutated in 11 out of 25 tumour samples, and genetic rearrangements near this gene were found in another nine patients.

This gene produces a protein that limits the action of another protein, PTEN, that prevents cancer development.  So, by limiting PTEN, you’re effectively allowing cancer to develop.

Potentially damaging PREX2 mutations were found in 14% of a further 107 tumours studied. Investigations in mice found that four of the six PREX2 mutations accelerated the development of melanoma in mice suggesting PREX2 might have a similar role in human melanoma.

The team also confirmed earlier findings that sun exposure effects the mutation rate of DNA. For example, tumours from areas of the body that are not frequently exposed to sunlight had around 3-14 mutations per million base pairs, while one patient, known to have had high levels of sun exposure, had 111 mutations per million base pairs.

The fact that signs of sun damage were seen in body areas that aren’t usually exposed to sunlight is especially important given the increasing rates of melanoma due to sun beds and indoor tanning.

This latest research is part of an ongoing project to improve our understanding of melanoma and to find more targets for treatment. A drug, Vemurafenib, which targets mutated BRAF protein in melanoma tumours, was approved by the US FDA last August.  The drug is very promising but can only help patients whose cancers contain the mutation that it targets, and whose tumours respond to the drug.

The identification of mutations in PREX2 is an important discovery that will improve our knowledge of the biological pathways that are disrupted in melanomas and could lead scientists to genes in other parts of those pathways that might be good drug targets.

For original article see here.

Images from here, here, and here.

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What distinguishes us from our primate-relatives?

We walk on two feet and lack hair-covered bodies, but what makes us ‘human’ is our brain which is capable of language, art, and science.

Pinpointing what caused our brains to be so different has been the goal of researchers ever since the first human and primate genomes were published.  Current research suggests that DNA duplication errors might have played a role in the evolution of the complex human brain.

Duplications happen when the enzyme that copies DNA slips extra copies of a gene into a chromosome. It has been estimated that duplications make up about 5% of the human genome.

Recently, the duplicated gene, SRGAP2, has been the focus of many research groups.  Four versions of this gene are found on chromosome 1, but they are not exact copies. All of the duplications are missing a small part of the ancestral form of the gene which is often the case with duplicated genes.

“Ten years after the human genome was sequenced and declared done, we’re still finding new genes in new places that are really important to human brain function and evolution,” says one of the researchers.

The duplication of SRGAP2 was calculated to have appeared ~ 2.4 million years ago, around the time that big-brained species of Homo evolved, and around the time that stone tools appeared in the fossil record. These ancient hominins eventually gave rise to Homo erectus, the first human ancestors to wander beyond Africa, ~ 1.8 million years ago.

Another research team went on to express the human form of SRGAP2 in the brains of developing mice. This didn’t cause the mice brains to enlarge, but their neurons (brain cells) produced denser connections with neighbouring neurons.

“If you’re increasing the total number of connections, you’re probably increasing the ability of this network to handle information….It’s like increasing the number of processors in a computer” says one of the researchers.

The SRGAP2 duplications are only one of a number of genetic changes that moulded the human brain. Geneticists have identified dozens of duplicated genes unique to humans, and many of them expressed in the brain.

“Finding the genes that make us human may be challenging…but the resources we now have to ask such questions are unprecedented.

For original article see here.

Images from here, here, and here.

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What makes dogs so amazing…

Man’s best friend is the most diverse animal on the planet – a staggering achievement considering most of the 350-400 dog breeds in existence have been around for only a couple hundred years.

What’s interesting about dogs is that breeders have fast-forwarded the normal pace of evolution.   The process of combining traits from different dogs and accentuating them by breeding those offspring with the desired attributes has led to an ‘artificial’ selection which favors single genes.

The huge range of dog shapes, colours, and sizes is caused, mostly, by changes in just a  handful of gene regions.  For example, the constrast between the dachshunds’ stumpy legs and a greyhounds sleek ones are determined by the sequence of a single gene.  If us humans varied as much as dogs, the smallest person would be two feet tall, the tallest 31 feet.  Normally, hundreds of genes interact to produce a physical trait in humans and most mammals.  Unusually, in dogs the magic number is usually three or fewer.

A group has analysed the DNA of 85 dog breeds and found that genetic similarities clustered them into four broad categories of Wolf-like, Herders, Hunters and Mastiff-like. Interestingly, behavioural traits such as the impulsive protectiveness of most dogs, remains a genetic mystery.

Where the striking diversity of dogs becomes handy is the fact that these isolated genetic populations are helping scientists to understand human genetic diseases.

Images from here, here and here.

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