The Sequence 11/28-12/4
Protein Interaction in Alzheimer’s Disease, Genetic Analysis and Ancestry of Upper Mesopotamians, A Way to Detect Cancer Before it Develops, Founder Mutation for a Genetic Form of Epilepsy Identified
Discovery on the importance of studying protein interaction in Alzheimer’s disease
Carlos Cruchaga worked to discover proteins associated with Alzheimer’s disease, and talks about his results in this interview with GenomeWeb.
Tell me more.
Cruchaga identified ~2,300 protein quantitative trait loci (pQTLs), or proteins associated with Alzheimer’s disease. Protein quantitative trait loci (pQTLs) are abundances of protein at certain spots in the gene. This is important because while plenty of GWAS studies (see more on how GWAS works here) have identified potential genetic variants associated with Alzheimer’s, it’s hard to prove if those variants actually have important functions. In other words, we don’t always know that it actually matters if there is a DNA change at a particular spot. But by being able to see which genetic variants are abundant in protein, we can get a better idea of whether a genetic mutation, or a harmful change in the DNA, in that location could cause Alzheimer’s disease. We would expect an abundance of protein to mean it is an important spot in the gene.
Cool. Anything else?
Yes! Just like we can find protein quantitative trait loci (pQTLs), we can similarly find expression quantitative trait loci (eQTLs), which are spots where the protein is expressed in the gene. See a post on protein expression, or epigenetics, here. So, by finding the overlap between where protein is located and where it’s expressed, Cruchaga’s work takes a big step in understanding genetic mutations, or harmful changes in the DNA, that cause known protein dysfunction and therefore Alzheimer’s disease.
What’s the takeaway?
Well, ultimately this is also a step in the direction of identifying a cure for Alzheimer’s- because where we know a cause, we can begin to try and find a treatment. Although we’re not able to change genes just yet, we’re able to change the expression of proteins. And we do it all the time. If we know that high levels of a certain protein are causing Alzheimer’s disease, we can create a drug that will block the pathway that allows that protein to express itself.
Pretty cool, huh?
Genetic analysis identifies ancestry of Upper Mesopotamians
Researchers used genomic analysis to identify the human remains of 14 individuals from Çayönü, in Turkey. The individuals studied lived about 8,500 to 7,500 BCE. The study helped to gain insights into the people living there during the Neolithic period.
Çayönü ruins, image credit Wikipedia
How?
To begin, genomic analysis helped the researchers to determine the ancestry of these individuals by comparing their DNA with published ancient genomes dating to c. 15,000 to 5500 BCE from the Fertile Crescent and neighboring regions.
Interesting. What did they find?
The research showed that Çayönü individuals shared ancestry with individuals of Central Anatolia, South Levant, and Central Zagros, suggesting a genetic blend from across the eastern and western Fertile Crescent.
Not surprising, because we already know that this area was involved in the Neolithic Transition, a shift from hunter-gatherer lifestyles to agricultural ones and related cultural changes. However, this confirms that this transition was likely made in part by Çayönü’s personal connections with diverse individuals across the wider region.
What’s the takeaway?
Integrating genetic and known archaeological data, these results illustrate the significant role Çayönü played as a cultural hub, contributing to human innovation on a large scale through not only their own ingenuity, but mobility with the surrounding areas.
A way to detect cancer before it develops
Researchers used cell-free DNA (cfDNA) analysis to identify biomarkers in the blood that seem to predict the development of cancer.
What is cell-free DNA?
Cell-free DNA (cfDNA) is essentially DNA that is released from cells into the circulatory system throughout the body. You may be familiar with cfDNA testing as it relates to noninvasive prenatal testing (NIPT), a now pretty standard test pregnant women receive to detect potential genetic conditions in their babies. This works because some of baby’s DNA is also floating around in pregnant mom’s blood.
Got it. What did they find?
Nicholas Cheng and collaborators used special sequencing developed by the team that looks at methylation patterns, and found cfDNA methylation signatures that were predictive of cancers years before the clinical diagnosis. They did this by testing samples from individuals with cancer that were collected as early as 7 years before the cancer was present, and comparing these samples to individuals without cancer.
The takeaway?
Researching protein biomarkers to predict cancer is not a new concept, but researching protein biomarkers in cfDNA is . This makes a difference because cfDNA can be analyzed with only a blood sample. It’s accessible, noninvasive, and can potentially detect tumor types that will develop. Not only will this technology help detect cancer sooner, it will give us insights into how tumors actually evolve over time.
Founder mutation for a genetic form of epilepsy identified
Grinton et al. looked into an autosomal dominant familial epilepsy syndrome known as ‘genetic epilepsy with febrile seizures plus’ (GEFS+), in order to understand the origin of the genetic condition. GEFS+ is a spectrum of seizure disorders of varying severity, from fever-induced seizures in infancy to a condition called Dravet syndrome in which individuals have prolonged seizures lasting several minutes and intellectual disability.
Tell me more.
The study looked at 14 independent families with GEFS+ who were found to have the same genetic cause, i.e. they all had the same mutation, or harmful change in the DNA, that caused epilepsy. They then compared their DNA with an additional 74 individuals with the same mutation from the UK Biobank.
Is it a coincidence they had the same mutation?
No. And that’s where i’m going with this. The team found that this one mutation is what we call a ‘founder mutation’. A founder mutation occurs when a group of people is culturally or geographically isolated, therefore sharing a large portion of their DNA. You’ve probably heard of how common mutations in BRCA1 and BRCA2 are: that’s because they have founder mutations. See my post on this here.
They were able to figure this out because the affected study participants all carried matching haplotypes (i.e. genes inherited together that indicate genetic origin), suggesting all instances of the variant derive from a single mutational event. The research suggests the variant arose in the late 1700s. The high frequency of the variant in the European cohort of the UK Biobank along with the ancestral origins identified supports a British origin of the variant, which then likely spread through settlement of Australia and the USA following migration from Britain.
What’s the takeaway?
So this is actually interesting because founder variants are rarely identified in early-onset autosomal dominant genetic conditions. Remember that autosomal dominant genetic conditions are caused by one gene mutation in one copy of a certain gene.
Why? Well because evolutionarily speaking, the earlier onset a genetic condition is, the less likely an individual is to procreate. Now, this condition is an exception because it’s not completely penetrant- meaning not everyone with the genetic mutation will be symptomatic.
This all means there’s a whole new frontier out there to discover the origins of well-described genetic conditions.