Genetic Lineage Contestation: Identity Query Unraveled
In 2003, as the human genome was sequenced, the floodgates were expected to open for a flurry of new therapies, with scientists pinpointing genes linked to diseases. But the process of translating genes into proteins proved to be more complex than anticipated.
The intricacy of gene regulation turned out to be astonishingly intricate. Not just genes themselves, but also proteins, RNA fragments, binding sites, and chemical groups interact with DNA to control protein production. Simplifying the relationship between an organism's genetic blueprint and its physical characteristics became a far more formidable challenge.
A recent study from MIT and the Whitehead Institute for Biomedical Research has added a fresh layer of complexity to this already complex conundrum. The researchers propose that biologists should consider an additional factor when attempting to explain the connection between genotype and phenotype: genetic material that doesn't originate from an organism's chromosomes.
Through ingenious lab experiments and meticulous analysis, the team exemplified this necessity in yeast cells. They demonstrated that deleting genes in these cells couldn't be fully understood without also considering non-chromosomal genetic material, particularly from mitochondria and viruses lurking in dividing cells.
"This discovery underscores the need to take a comprehensive approach when analyzing human genetics," says David Gifford, a professor at MIT. "We need to comprehend the extent to which viruses are transmitted from parent to offspring and understand the spectrum of mitochondria present in humans, their potential interactions with chromosomal mutations."
The study germinated from a typical attempt to analyze a specific group of yeast genes, by comparing the growth rates of yeast colonies with and without deletions. Surprisingly, the growth rates of colonies with deletions were inconsistent: sometimes they were as vigorous as the normal yeast cells, other times they were significantly slower, often falling somewhere in between.
"We kept encountering inconsistencies, and we discovered that as experiments progressed, this double-stranded RNA virus was being lost in certain strains, despite having a significant impact when present," Gifford explains. "This led us to wonder if other non-chromosomal genetic elements could be impactful, and that's when we began looking at mitochondria."
Mitochondria, often referred to as the 'cellular powerhouse' due to their role in energy production, are a peculiarity that can be found in almost all plant, animal, and fungal cells. Despite being integral components, they have their own distinctive genomes, which are separate from their host's cellular DNA.
The emergence of mitochondria traces back to a symbiotic relationship with early life forms. According to current theories, they were initially free-living bacteria that formed a mutually beneficial alliance with ancient life forms.
The team at MIT and the Whitehead Institute further discovered that the consequences of deleting genes in yeast cells could not be fully explained without considering mitochondrial DNA.
"Our collaborators designed a clever method of swapping mitochondria between yeast strains, allowing us to examine their exact impact," says Gifford. "This reciprocal exchange revealed that mitochondrial DNA played a significant role in determining the growth rates of yeast colonies."
Gerald Fink, a professor at MIT and a researcher from the Whitehead Institute, delved deeper and removed the mitochondria from one yeast cell, which then mated with a cell from a different strain. Fink prevented the cells' nuclei from fusing and forced the new cell containing two nuclei to divide, giving rise to a new strain with a nucleus from one yeast strain combined with the mitochondria of the other.
For each genetic deletion the team studied, they created strains in which the nuclear state—gene deleted or left intact—was combined with various different types of mitochondria. They also produced variations with and without infections from the virus.
The results demonstrated a combined effect of genetic deletions and variations in mitochondrial DNA or the presence of the virus. Gene deletion alone accounted for approximately 40% of the variation in yeast colonies' growth rates. However, when combined with a broad categorization of strains based on non-chromosomal material, the team could explain the remaining 60%.
A more sophisticated mathematical model posited a nonlinear interaction between the virus and specific strains of mitochondria. This model elucidated almost 90% of the variation in growth rates, not only for colonies with deleted genes but for naturally occurring yeast cells as well.
"Initially, we thought that the effects of the chromosomal modification and the effect of the virus were independent," Gifford says. "But we found that they were synergistic. This study suggests that we should also be looking for heritability in regions that are not part of the chromosomal DNA."
Eran Segal, a professor at the Weizmann Institute in Israel, agrees: "There's anecdotal evidence that we'll see similar things in humans." Biologists may have overlooked simpler heritable factors by focusing on rarer variants and combinations, he contends. However, the MIT study emphasizes that exploring non-chromosomal genetic material may offer a more readily accessible approach to explaining missing heritability.
- The research from MIT and the Whitehead Institute has demonstrated that genetic material outside an organism's chromosomes can significantly affect the connection between genotype and phenotype, as shown in their study on yeast cells.
- The team's discovery underscores the need to consider the impact of viruses and mitochondria on gene regulation and protein production when analyzing human genetics.
- Mitochondria, often referred to as the 'cellular powerhouse', have their own distinctive genomes, separate from their host's cellular DNA, and play a significant role in determining physical characteristics.
- The study suggests that researchers should also look for heritability in regions that are not part of the chromosomal DNA, as the effects of non-chromosomal genetic material may help explain missing heritability.
- The research on yeast cells has shown that the growth rates of yeast colonies cannot be fully understood without considering both chromosomal and non-chromosomal genetic material, specifically mitochondrial DNA and viral infections.
- Biologists may have overlooked simpler heritable factors by focusing primarily on rarer variants and combinations, as exploring non-chromosomal genetic material could offer a more readily accessible approach to understanding complex phenomena in health and wellness, fitness and exercise, mental health, and nutrient absorption.
