Study explains “dark” portion of human genome implicated in various disorders

A “dark” part of the human genome has puzzled researchers for many years, similar to an enigmatic dark matter that accounts for 85% of the universe.

Clemson Professors Trudy Mackay and Robert Anholt address human genetics questions by studying the common fruit fly, Drosophila melanogaster, because many genes are conserved between humans and fruit flies, meaning research results can be extrapolated to human health and disease. Image Credit: College of Science.

Now, a research recently published in the Genome Research journal on March 9^th, 2020, has detected new parts of the fruit fly genome that have been concealed in these silent, dark regions, until now.

The collaborative study titled “Gene Expression Networks in the Drosophila Genetic Reference Panel” was the result of years of studies performed by geneticists Trudy Mackay and Robert Anholt from Clemson University. The revolutionary findings of the researchers could considerably improve science’s interpretation of several genetic disorders.

The “dark” part alludes to approximately 98% of the genome that seems to lack any evident function, while just 2% of the human genome codes for proteins. Proteins are not only the building blocks of human bodies, but they are also the catalysts of the chemical reactions enabling humans to thrive.

This concept has long perplexed researchers since the 1970s when advanced gene sequencing technologies were initially created and exposed the level of coding to noncoding genomic regions.

Traditionally, genes are believed to be transcribed into RNAs, which are later converted into proteins, as governed by the central dogma of molecular biology. But the whole assembly of RNA transcripts within the genome, known as the transcriptome, comprises RNA species that, aside from coding for proteins, seems to have other functions.

A few have suggested that regulatory regions could be present in noncoding regions, regulating the structure of chromosomes and genetic expression. But such theories were not easy to study previously because diagnostic technology was merely under development.

Only in recent years, with the sequencing of the entire transcriptome complete, have we realized how many RNA species are actually present. So, that raises the whole new question: if they aren't making the proteins—the work horses of the cell—then what are they doing?”

Trudy Mackay, Geneticist and Director, Center for Human Genetics, Clemson University

Center for Human Genetics is part of the College of Science.

For both Mackay and Anholt, also from the Center for Human Genetics, such human genetics questions can be explored by analyzing Drosophila melanogaster—the common fruit fly.

Since several genes are preserved between fruit flies and humans, study findings showed that the genome can be extrapolated to human health and disease by studying the Drosophila.

This new study was headed by Mackay and Anholt’s former postdoctoral scientists, Logan Everett and Wen Huang. The study detected over 4,500 new transcripts in Drosophila melanogaster that have never been exposed in the past. These 4,500 transcripts are dubbed “novel transcribed regions” by the scientists. They mainly contain noncoding RNAs that seem to play a role in controlling gene networks and could possibly account for genetic disorders.

Most disease-causing mutations are known to occur in the protein-coding portion of the genome, known as the exome, but when you're only sequencing the exome, you miss other disease-related factors in other parts of the genome, such as these long noncoding RNAs.”

Robert Anholt, Geneticist and Provost’s Distinguished Professor, Department of Genetics and Biochemistry, Clemson University

Anholt continued, “Now that the cost of whole-genome sequencing has gone down considerably, and we have the capability of sequencing whole genomes rapidly, we can look at elements of the genome that have traditionally been considered unimportant, and we can identify among them potential disease-causing elements that have never been seen before.”

By studying hundreds of inbred Drosophila fly lines, each comprising individuals that are almost genetically identical, the scientists found that a majority of the new long noncoding RNAs control genes in heterochromatin. Heterochromatin is a densely packed form of DNA in the genome that is often believed to be “silent.”

Since heterochromatin is extremely condensed, it was assumed that molecular machinery could not access this form of DNA. Molecular machinery is known to transcribe DNA into RNA.

Hence, any genes present within heterochromatin are silent, kept off, and not expressed, or are they?

What we think is that the repression of gene expression in heterochromatin is somewhat leaky, and that there is variation in how those genes are repressed. The network of RNAs we’ve discovered may have to do with actually regulating chromatin state.”

Trudy Mackay, Geneticist and Director, Center for Human Genetics, Clemson University

“These noncoding RNAs may play an important role in opening up such regions of the genome for expression of genes in a way that varies among different individuals depending on their genetic background,” added Anholt.

Yet another result of the study is the expression of “jumping genes,” called transposons. These genes are parts of DNA that move around the genome. When these transposons cut and paste into other types of genes, they are likely to cause genome instability that results in neurodegenerative disorders, cancer, and many other disorders.

While these transposons were also situated in heterochromatin, the detection of transcripts of these transposons demonstrates that they are in fact, being expressed, in spite of residing in a tipsily silent part of the genome. Detecting regulators of transposable elements, as the scientists noted among these 4,500 “novel transcribed regions,” may prove handy in treating various disorders that arise from the interference of transposons.

On the whole, the research lends toward a better insight into gene regulatory networks that play a role in human health and disease.

“These observations open up an entirely new area of biology that hasn't been explored and has unlimited potential for future follow-up,” added Anholt.

The researchers’ own follow-up research is utilizing CRISPR gene-editing technology to reveal what exactly occurs when genes shown in this analysis are deleted or changed from the Drosophila genome. If the expression of other kinds of genes is modified by knocking out one gene, major conclusions can be reached about the role played by the deleted gene in the progression or development of diseases.