Wednesday, February 17, 2016

In my human genes: history, identity, fate

Written by Jae Joseph Russell Rodriguez (Ribozymes)

Three months ago, I found myself on the shores of Brač, an island off the coast of southern Croatia. While it was the perfect time of the year to enjoy the Mediterranean summer in such a historic place, my reason for taking the long journey was more professional than leisurely. I came as the only Filipino delegate to the 9th International Society for Applied Biological Sciences (ISABS) Conference. It was a week-long scientific meeting with a tripartite theme of anthropological, forensic, and medical genetics. I personally would like to think that my participation marked my transition, from a more forensic background during my master’s to a possible PhD track on anthropological genetics. It was an excellent venue for interaction among students and scientists from these three allied fields. New friends, delightful wine, sand, sun, and the Adriatic Sea, but most rewarding were the excellent and most up to date discussions on human DNA and its applications. I briefly summarize here my musings with the Philippines always put into context.

In our DNA is information. Within the variability in nucleotide sequence are the nuances of how we should develop, how we should look like, and how certain functions are carried out in our cells. In addition to these are archives of information that allow us to peer back into our history as a species, to look at the unique fingerprints of our identity, and possibly even to gaze into the fates our bodies are in store for us. While simply knowing these things hold us in awe, human genetics has the immense potential to benefit humanity, and in particular to serve Filipinos in many ways more than what we can imagine.

Digging up the past through anthropological genetics

In our DNA is a story. It is a story of how our species connects with our 7 million year old ancestor we share with are closest cousin, the chimpanzee. Through genome sequencing technology we know that we share about 94 percent of our DNA with chimps, greater than the proportion they share with either gorillas or orangutans. Perhaps, knowledge of our genomes may also help us to deal more kindly with one another. Despite all our differences in color (be it skin, creed, or political), we humans are about 99 percent alike in our DNA.

It is also a story of how our ancestry goes back to the African continent. The DNA in our mitochondria due to its strict maternal inheritance can be traced to a single woman nicknamed mitochondrial Eve that lived in Africa about a hundred thousand years ago. Likewise, the Y-chromosome of males, passed on from father to son, converge to a man which also lived in Africa, and we call him Y-chromosomal Adam. However, this is not to say that this “Adam” and “Eve” were the first and only humans when they were alive, neither they had even met and overlapped lifetimes. The Y-chromosome and the mitochondrial DNA are just but a tiny proportion of the entire human genome. That they are transmitted down exclusively uniparental lines enables geneticists to study them without the complications of recombination. Yet, in our 22 autosomes are patches of ancestries shuffled through several thousand generations. While such massive genome-wide information demands more complicated analyses, it is a treasure trove of richer and more complete accounts of our history.

When our ancestors ventured out of Africa, they were confronted with diverse challenges in new environments. Today we find this as signatures in the DNA of certain populations that have adaptive advantages, for example immunity to certain diseases or ability to withstand low oxygen conditions. Our ancestors also met face to face with other species of humans and likely interbred with them. Whole genome sequences reveal that all non-Africans possess some DNA from Neanderthals. More recently, it was found that Papua New Guineans, Australian aborigines, and even some Filipinos such as the Mamanwa derive some ancestry from Denisovans, human species first discovered in Denisova cave in Siberia through tooth and finger bone remnants.

Genetic studies, interpreted in the light of linguistics, archaeology, and anthropology, have extensively provided insights on how humans came to populate the globe in six continents. In the Philippines, there were already a number of studies on our indigenous peoples as well as the general population that mostly focused on the mitochondrial and Y-chromosomal DNA. These studies reveal that we Filipinos derive much of our ancestry from the migration of Austronesian speaking farmers from Taiwan. This discredits the obsolete theory by H. Otley Beyer (still taught in elementary schools) that the Philippines had been peopled by successions of Negritos, Indonesians, and Malays. With the archipelago situated in such a strategic location in the Pacific and home to over 170 unique ethnolinguistic groups of diverse cultures and backgrounds, there is still much to learn and unravel about our roots.

Seeking answers to questions of identity through forensic genetics

Forensic genetics takes advantage of the different DNA markers throughout genome whose variable mutation rates, levels of diversity, and modes of inheritance allow us to answer questions of legal interest. The most commonly used markers are autosomal short tandem repeats (STRs) due to their high levels of variability and ease of detection through PCR technology. In criminal investigations, for example, a DNA match between a suspect and the evidence at just 20 or more markers may lead to the person’s identification as the actual perpetrator beyond reasonable doubt. Y-chromosomal markers, on the other hand, are employed in detecting male DNA in sexual assault specimens and also in determining paternal relatedness between male individuals. The mitochondrial DNA (mtDNA) due to its stability and high copy number in cells is used in analyzing severely degraded samples, for example in disaster victim identification. Maternal inheritance also makes it useful in establishing relatedness in a maternal line.

The emerging picture is the increasing impact of next generation sequencing (sometimes referred to as “now” generation sequencing) to DNA forensics. Platforms and methods are rapidly being developed to increase sensitivity in analyzing trace and degraded samples, increasing power of discrimination by al-lowing simultaneous analysis of several markers, and even inferring ancestry and phenotypes (for example, eye and hair color) of the source of a sample.

DNA is the most powerful and objective tool for identification given that no two individuals (with the exception of identical twins) share the same DNA sequence. In developed countries around the globe, the use of DNA evidence is incorporated into the criminal justice system. The number of reported cases of heinous crimes continue to rise in our country yet DNA testing is not being routinely done due to the absence of a law mandating this. This despite our local forensic laboratories being capable of conducting such tests. To date, majority of cases are still litigated solely through testimonial evidence which may be prone to bias or fraud. It is for our legislators to recognize this as an urgency for the benefit of Filipinos who might be victims of heinous crimes and even of wrongful convictions.

Circumventing our clinical fate through medical genetics

Human disorders that have genetic bases constitute a broad spectrum. Among these are congenital errors of metabolism and hemoglobinopathies which may cause early death or mental retardation if not detected shortly after birth. Our country has the National Comprehensive Newborn Screening System (NCNBSS) established under RA 9288 to provide the opportunity to every baby born in the Philippine to undergo newborn screening to prevent mental retardation, early death, and allow for early management of a genetic disease. Originally, five disorders were being tested namely, congenital hypothyroidism, congenital adrenal hyperplasia, phenylketonuria, galactosemia, and glucose-6-phosphate dehydrogenase deficiency. This has recently been expanded to include 22 additional inborn errors of metabolism and hemoglobin.

Diagnosis and treatment of genetic disorders increasingly benefit from the rapid development of sequencing technology and its staggering drop in cost. Recent years have seen refinement in the detection of germline mutations that cause rare Mendelian disorders, identification of tumor- and stage-specific mutations in cancer, and discovery of genomic regions associated with diseases with complex patterns of inheritance. Epigenetics also emerges into the picture due to the increasing awareness of its significance in disease progression. Overall, the trend is a shift from a traditional one-size-fits-all approach to treatment to individualized medicine that considers the complex interactions across a patient’s unique genome, epigenome, and environment.

Despite the burgeoning applications of genomics to medicine in developed countries, genetic disorders among Filipino patients continue to receive inadequate attention due to our shortage in clinical geneticists and genetic counselors. This should encourage some of our younger generation of geneticists to pursue further education and research in this actively developing field.#




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Mr. Jae Joseph Russell Rodriguez (BS Biology, cum laude, 2007; MS Genetics, 2015) has been teaching genetics and cell biology at the Institute of Biological Sciences, UP Los Baños since 2007. He is an alumnus and the current Junior Faculty Adviser of The UPLB Genetics Society.

First published in print (GENEWS October 2015 Issue)

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