Using zebrafish, researchers at Duke University Medical Center have identified genes responsible for head size at birth.
Head size in human babies is a feature that is related to autism, a condition that recent figures have shown to be more common than previously reported, 1 in 88 children in a March 2012 study.
Head size is also a feature of other major neurological disorders, such as schizophrenia.
“In medical research, we need to dissect events in biology so we can understand the precise mechanisms that give rise to neurodevelopmental traits,” said senior author Nicholas Katsanis, Ph.D., Jean and George Brumley Jr., MD, Professor of Developmental Biology, and Professor of Pediatrics and Cell Biology.
“We need expert scientists to work side by side with clinicians who see such anatomic and other problems in patients, if we are to effectively solve many of our medical problems,” he stated.
Katsanis knew that a region on chromosome 16 was one of the largest genetic contributors to autism and schizophrenia, but a conversation at a European medical meeting pointed him to information that changes within that same region of the genome also were related to changes in a newborn’s head size.
The problem was difficult to address because the region had large deletions and duplications in DNA, which are the most common mutational mechanisms in humans.
“Interpretation is harrowingly hard,” said Katsanis, who is also director of the Duke Center for Human Disease Modeling.
The reason is that a duplication of DNA or missing DNA usually involves several genes.
“It is very difficult to go from ‘here is a region with many genes, sometimes over 50’ to ‘these are the genes that are driving this pathology,’“ Katsanis said.
“There was a light bulb moment. The area of the genome we were exploring gave rise to reciprocal (opposite) defects in terms of brain cell growth, so we realized that overexpressing a gene in question might give one phenotype ?" a smaller head, while shutting down the same gene might yield the other, a larger head,” he explained.
The researchers transplanted a common duplication area of human chromosome 16 known to contain 29 genes into zebrafish embryos and then systematically turned up the activity of each transplanted human gene to find which might cause a small head (microcephaly) in the fish. They then suppressed the same gene set and asked whether any of them caused the reciprocal defect: larger heads (macrocephaly).
The researchers knew that deletion of the region that contained these 29 genes occurred in 1.7 percent of children with autism.
It took the team a few months to dissect such a “copy number variant” ?" an alteration of the genome that results in an abnormal number of one or more sections of chromosomal DNA.
“Now we can go from a genetic finding that is dosage-sensitive and start asking reasonable questions about this gene as it pertains to neurocognitive traits, which is a big leap,” Katsanis said.
Neurocognitive refers to the ability to think, concentrate, reason, remember, process information, learn, understand and speak.
Many human conditions have anatomical features that are also related to genetics, he said. “There are major limitations in studying autistic or schizophrenic behavior in zebrafish, but we can measure head size, jaw size, or facial abnormalities.”
The single gene in question, KCTD13, is responsible for driving head size in zebrafish by regulating the creation and destruction of new neurons (brain cells). This discovery let the team focus on the analogous gene in humans.
“This gene contributes to autism cases, and probably is associated with schizophrenia and also childhood obesity,” Katsanis said.
Once the gene has been uncovered, researchers can examine the protein it produces. “Once you have the protein, you can start asking valuable functional questions and learning what the gene does in the animal or human,” Katsanis said.
Copy number variants, such as the ones this team found on chromosome 16, are now thought to be one of the most common sources of genetic mutations. Hundreds, if not thousands, of such chromosomal deletions and duplications have been found in patients with a broad range of clinical problems, particularly neurodevelopmental disorders.
“Now we may have an efficient tool for dissecting them, which gives us the ability to improve both diagnosis and understanding of disease mechanisms,” Katsanis said.
The current study suggests that KCTD13 is a major contributor to some cases of autism, but also points to the synergistic action of this gene with two other genes in the region, named MVP and MAPK3, Katsanis said.
The study was published online in Nature journal on May 16.
Genes Behind Stuttering Found
LiveScience Staff
Date: 10 February 2010 Time: 12:00 PM ET
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| The epigenome is a molecular marking system that controls gene expression without altering the DNA sequence. In a sense, the epigenome is the genome's boss. Image CREDIT: Dreamstime |
Stuttering may have genetic underpinnings, according to a new study. For the first time, scientists have identified specific genetic alterations that they believe play a key role in giving rise to the speech disorder.
These alterations, or mutations, are located on three particular genes, and are thought to cause a glitch in the way cells dispose of cellular "garbage."
"For hundreds of years, the cause of stuttering has remained a mystery for researchers and health care professionals alike, not to mention people who stutter and their families," said Dr. James F. Battey, Jr., director of the National Institute on Deafness and Other Communication Disorders (NIDCD), the organization that led the study. "This is the first study to pinpoint specific gene mutations as the potential cause of stuttering," and might lead to an expansion in treatment options, he said.
The results were published online Feb. 10 in the New England Journal of Medicine.
Stuttering is a speech disorder in which a person repeats or prolongs sounds, syllables, or words, disrupting the normal flow of speech. The result can severely hinder communication. Most children who stutter outgrow it, although many do not; roughly 1 percent of adults stutter worldwide. Current therapies for adults who stutter have focused on such strategies as reducing anxiety, regulating breathing and rate of speech, and using electronic devices to help improve fluency.
Stuttering tends to run in families, and researchers have long suspected a genetic component. Previous studies of a group of families from Pakistan pointed to chromosome 12 as a site that may be involved in the disorder. (A chromosome is a long sequence of DNA that contains many genes.)
In the current study, researchers took a closer look at this chromosome. They identified mutations in a gene known as GNPTAB in the affected family members. The GNPTAB gene is carried by all higher animals, and gives cells instructions for making an enzyme that assists in breaking down and recycling cellular components.
They then analyzed the genes of 123 Pakistani individuals who stutter — 46 from the original families and 77 who are unrelated — as well as 96 unrelated Pakistanis who don't stutter, and who served as controls. Individuals from the United States and England also took part in the study, 270 who stutter and 276 who don't. The researchers found some individuals who stutter possessed the same mutation as that found in the large Pakistani family.
The scientists then looked at two other genes which are closely tied to the role of GNPTAB. They found individuals who stuttered showed mutations in these genes while control groups did not.
Several of the newly identified "stuttering genes" are thought to contribute to certain metabolic disorders. People with these disorders cannot properly break down cell waste, causing deposits to build up in their cells. These deposits can ultimately cause health problems in the body's joints, skeletal system, heart and liver, as well as developmental problems in the brain. They are also known to cause problems with speech.
So why don't people who stutter also have these metabolic disorders? For many of these metabolic diseases, a person needs to have two defective copies of a gene, said study author Dennis Drayna, a geneticist with the NIDCD. But in the current study, nearly all of the unrelated individuals who stuttered had only one copy of the mutated gene, he said.
The findings open new research avenues into possible treatments for stuttering. For example, current treatment methods for some metabolic disorders involve injecting a manufactured enzyme into a person's bloodstream to replace the missing enzyme. The researchers wonder if enzyme replacement therapy might be a possible method for treating some types of stuttering in the future.
Right now, about 9 percent of people who stutter are known to possess mutations in one of the three genes, the researchers say. Next, they plan to conduct a worldwide study to better determine the number of people who carry these mutations. A long-term goal is to better understand how metabolic defects may affect structures within the brain that are essential for fluent speech.
The Genetics of Eye Color
A person's eye color is determined by the genes inherited from their parents. The types of alleles received from the parents are assigned to certain chromosomes. The dominant genes are expressed and the recessive genes are hidden. In the development of the iris those genes tell enzymes to produce and place a certain amount of melanin in the iris to form the eye color.
Genes are particles that get inherited.
Humans have several eye color genes. Two of these genes are named bey2 (brown eye) and gey (green eye).
Genes come in flavors called alleles.
The bey2 gene has two flavors - brown and blue.
The gey gene also has two flavors - green and blue.
Genes are on chromosomes. There is one copy of the gene on each chromosome (some genes also come in many copies).
Chromosomes come in pairs.
Thus each individual has two copies of each gene. These two copies can be the same flavor (allele) or different flavors.
Genes are used to produce proteins. A gene that comes in two flavors might come in one flavor where the protein works correctly and another flavor in which the protein does not work. Thus an individual with one copy of the good flavor and one copy of the defective flavor for a gene could still produce a protein that worked.
Eye Color Calculator
So what is going on here?
(An explanation for our interactive eye color genetics calculator)
- Eye colors are distinct (brown, green, blue) rather than mixed. If we mixed green and blue paints we would get a greenish-blue paint. Mixing in brown would give mud. Eye colors of children came out as pure green, blue, or brown, not as a mixture of the colors of their parents' eyes.
- Eye color acts like distinct particles are inherited - one can have the particle for green eyes or the particle for blue eyes.
- Children can have different eye colors than either of their parents. This is strange, if colors can't mix. It would make sense if colors mixed and blue and green eyed parents had greenish-blue eyed children.
- Brown tends to swamp out green, green tends to swamp out blue.
- A parent with brown-brown genes produces only children with brown eyes, but a parent with brown-blue eyes could produce children with eye colors other than brown.
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| An individual with brown and blue alleles of the bey2 gene on chromosome 15. There are two copies of chromosome 15. Each copy has the bey2 gene. On one copy the bey2 gene is in the brown flavor, in the other the bey2 gene is in the blue flavor. The difference between the brown and blue alleles is due to some difference in the genetic code for each gene (the DNA sequence for the bey2 gene isn't yet known). |
Humans have several eye color genes. Two of these genes are named bey2 (brown eye) and gey (green eye).
Genes come in flavors called alleles.
The bey2 gene has two flavors - brown and blue.
The gey gene also has two flavors - green and blue.
Genes are on chromosomes. There is one copy of the gene on each chromosome (some genes also come in many copies).
Chromosomes come in pairs.
Thus each individual has two copies of each gene. These two copies can be the same flavor (allele) or different flavors.
Genes are used to produce proteins. A gene that comes in two flavors might come in one flavor where the protein works correctly and another flavor in which the protein does not work. Thus an individual with one copy of the good flavor and one copy of the defective flavor for a gene could still produce a protein that worked.
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