Surprise Grows Over Importance of Previously Dismissed Portions of the Genome
Evolution News & Views
We've often pointed out how the collapse of the junk-DNA concept fulfills intelligent-design predictions while falsifying Darwinism. At the risk of being repetitive, it is important to keep reporting the latest evidence, for the benefit of holdouts.
In the past, we have seen indirect evidence for function, finding that large portions of non-coding DNA are indeed transcribed, as shown by the ENCODE project. Further indirect evidence has come to light as knockout experiments of non-coding regions harm or kill the organism. In a few cases, direct evidence of function has been shown by analyzing the role of certain RNA transcripts of non-coding DNA. Here are two more examples of indirect and direct evidence.
Indirect Evidence: Don't Vary the Repeats
News from Duke University announces, "Variation in 'Junk' DNA Leads to Trouble." Trouble, indeed: "unstable genomes, cancer, and other defects." That's what they found can happen when apparently worthless repetitive sequences around centromeres are varied. First, however, notice the shift in outlook:
Although variants are scattered throughout the genome, scientists have largely ignored the stretches of repetitive genetic code once dismissively known as "junk" DNA in their search for differences that influence human health and disease.
A new study shows that variation in these overlooked repetitive regions may also affect human health. These regions can affect the stability of the genome and the proper function of the chromosomes that package genetic material, leading to an increased risk of cancer, birth defects and infertility. The results appear online in the journal Genome Research.
"Variation is not only important for how genes and proteins function, but it can also occur in the noncoding, repetitive portions of the genome," said Beth A. Sullivan, Ph.D., senior author of the study and associate professor of molecular biology and microbiology at Duke University School of Medicine.
"What we found in this study is probably the tip of the iceberg," Sullivan said. "There could be all sorts of functional consequences to having variation within the complex, repetitive portion of the genome that we don't know about yet." [Emphasis added.]
Centromeres are the junctions where two chromosomes connect. Associated with the centromeres is a region of "satellite DNA" that looks monotonous -- "blocks of exactly 171 A's, C's, T's and G's, repeated over and over for millions of base-pairs." Apparently this region acts as a landing pad for the centromere. Sullivan found, however, that some chromosomes have more than one such region. In some individuals, the centromere can form at either spot. Sullivan wanted to learn about the difference; is one spot better than the other?
The answer appears to be yes, at least for chromosome 17 which she studied. One site is the primary, the other the backup. If the primary site has a variation, the cell may use the backup site for the centromere. The backup site is not as good, though, the news item says.
Most of the time, the centromeres aren't built at the primary site if it contains variation and instead are assembled at the "backup" site nearby. But when this happens, the result may be a dysfunctional centromere that is architecturally unsound and an unstable chromosome that may be present in too many or too few copies.
"It is immensely fascinating to think that there are so many people walking around who are essentially centromere mosaics," said Sullivan. "One of their centromeres, on one of their chromosomes, has the potential to be dangerously unstable, and it could affect their ability to reproduce, or predispose them to cancer."
This, then, constitutes an example of indirect support for function. What looks like a useless stretch of repetitive DNA cannot tolerate much variation. The Abstract in Genome Research summarizes the finding:
Our study demonstrates that genomic variation within highly repetitive, non-coding DNA of human centromere regions has a pronounced impact on genome stability and basic chromosomal function.
As she said earlier, this particular finding is probably the "tip of the iceberg" for similar discoveries to come. Other "complex, repetitive" portions of the genome should not be dismissed; the search is on for more function in the junk-tion. So who were the science stoppers back when? The ones who "largely ignored the stretches of repetitive genetic code once dismissively known as 'junk' DNA."
Direct Evidence: Glimpsing a Multi-Functional lncRNA
Long non-coding RNAs (lncRNA) used to be on the genetic junk pile. As we have seen before, they can be indispensable. Last year we took a brief look at a particular lncRNA named Xist, involved in X-chromosome silencing in the female (i.e., only one X chromosome can be active at a time, so the other must be inactivated). More information has come to light about this lncRNA's structure and function. A new paper in the Proceedings of the National Academy of Sciences (PNAS) says this about the functional existence of Xist:
Long noncoding RNAs (lncRNAs) are important regulators of gene expression, but their structural features are largely unknown. We used structure-selective chemical probing to examine the structure of the Xist lncRNA in living cells and found that the RNA adopts well-defined and complex structures throughout its entire 18-kb length. By looking for changes in reactivity induced by the cellular environment, we were able to identify numerous previously unknown hubs of protein interaction. We also found that the Xist structure governs specific protein interactions in multiple distinct ways. Our results provide a detailed structural context for Xist function and lay a foundation for understanding structure-function relationships in all lncRNAs.
The current study, therefore, is another "tip of the iceberg" case that has implications for all lncRNAs. In this case, the researchers from University of North Carolina at Chapel Hill identified "complex well-defined secondary structure domains" in this 18,000-base RNA molecule that are related to specific functions.
The Xist RNA structure modulates protein interactions in cells via multiple mechanisms. For example, repeat-containing elements adopt accessible and dynamic structures that function as landing pads for protein cofactors. Structured RNA motifs create interaction domains for specific proteins and also sequester other motifs, such that only a subset of potential binding sites forms stable interactions. This work creates a broad quantitative framework for understanding structure-function interrelationships for Xist and other lncRNAs in cells.
A landing pad has a function, does it not? Think of an airport's landing strip with all the repeating lines down the center. Those repeats have a purpose, just as they do in Xist. Protein cofactors look for them to land on. Other proteins look for spots to take action, like markings on the stage floor for actors.
This RNA, once considered junk because it doesn't code for protein, has been elevated to a regulator of multiple important functions. Its shape tells other proteins where to land, where to interact, and what places to avoid. That shape is determined by the non-coding DNA that confers precise structures to the lncRNA. "Fully one-half of the Xist lncRNA forms well-defined structure motifs," the authors say. Anybody want to bet the other half will prove just as vital?
The authors feel their findings create a treasure hunt for further investigation into functions in the structure of lncRNAs. Or, to borrow another metaphor of theirs, it's time to listen to what the orchestra is playing.
The structured and unstructured domains identified here define maps that are expected to be invaluable in guiding investigations into the mechanisms by which Xist elements contribute to X chromosome inactivation. Xist and other lncRNA transcripts may span kilobases to coordinate long-range protein and domain interactions (Figs. 3 and 4) that ultimately enable orchestration of epigenetic regulation on the kilobase to megabase scales. Many lncRNAs are likely to share features identified here for Xist, including densely arrayed secondary structural features, multiple distinctive modes of protein interaction, and the ability to serve as multidomain organizers of cellular function.
Yes, there's function in the junk-tion, and it's music to our ears.
Evolution News & Views
We've often pointed out how the collapse of the junk-DNA concept fulfills intelligent-design predictions while falsifying Darwinism. At the risk of being repetitive, it is important to keep reporting the latest evidence, for the benefit of holdouts.
In the past, we have seen indirect evidence for function, finding that large portions of non-coding DNA are indeed transcribed, as shown by the ENCODE project. Further indirect evidence has come to light as knockout experiments of non-coding regions harm or kill the organism. In a few cases, direct evidence of function has been shown by analyzing the role of certain RNA transcripts of non-coding DNA. Here are two more examples of indirect and direct evidence.
Indirect Evidence: Don't Vary the Repeats
News from Duke University announces, "Variation in 'Junk' DNA Leads to Trouble." Trouble, indeed: "unstable genomes, cancer, and other defects." That's what they found can happen when apparently worthless repetitive sequences around centromeres are varied. First, however, notice the shift in outlook:
Although variants are scattered throughout the genome, scientists have largely ignored the stretches of repetitive genetic code once dismissively known as "junk" DNA in their search for differences that influence human health and disease.
A new study shows that variation in these overlooked repetitive regions may also affect human health. These regions can affect the stability of the genome and the proper function of the chromosomes that package genetic material, leading to an increased risk of cancer, birth defects and infertility. The results appear online in the journal Genome Research.
"Variation is not only important for how genes and proteins function, but it can also occur in the noncoding, repetitive portions of the genome," said Beth A. Sullivan, Ph.D., senior author of the study and associate professor of molecular biology and microbiology at Duke University School of Medicine.
"What we found in this study is probably the tip of the iceberg," Sullivan said. "There could be all sorts of functional consequences to having variation within the complex, repetitive portion of the genome that we don't know about yet." [Emphasis added.]
Centromeres are the junctions where two chromosomes connect. Associated with the centromeres is a region of "satellite DNA" that looks monotonous -- "blocks of exactly 171 A's, C's, T's and G's, repeated over and over for millions of base-pairs." Apparently this region acts as a landing pad for the centromere. Sullivan found, however, that some chromosomes have more than one such region. In some individuals, the centromere can form at either spot. Sullivan wanted to learn about the difference; is one spot better than the other?
The answer appears to be yes, at least for chromosome 17 which she studied. One site is the primary, the other the backup. If the primary site has a variation, the cell may use the backup site for the centromere. The backup site is not as good, though, the news item says.
Most of the time, the centromeres aren't built at the primary site if it contains variation and instead are assembled at the "backup" site nearby. But when this happens, the result may be a dysfunctional centromere that is architecturally unsound and an unstable chromosome that may be present in too many or too few copies.
"It is immensely fascinating to think that there are so many people walking around who are essentially centromere mosaics," said Sullivan. "One of their centromeres, on one of their chromosomes, has the potential to be dangerously unstable, and it could affect their ability to reproduce, or predispose them to cancer."
This, then, constitutes an example of indirect support for function. What looks like a useless stretch of repetitive DNA cannot tolerate much variation. The Abstract in Genome Research summarizes the finding:
Our study demonstrates that genomic variation within highly repetitive, non-coding DNA of human centromere regions has a pronounced impact on genome stability and basic chromosomal function.
As she said earlier, this particular finding is probably the "tip of the iceberg" for similar discoveries to come. Other "complex, repetitive" portions of the genome should not be dismissed; the search is on for more function in the junk-tion. So who were the science stoppers back when? The ones who "largely ignored the stretches of repetitive genetic code once dismissively known as 'junk' DNA."
Direct Evidence: Glimpsing a Multi-Functional lncRNA
Long non-coding RNAs (lncRNA) used to be on the genetic junk pile. As we have seen before, they can be indispensable. Last year we took a brief look at a particular lncRNA named Xist, involved in X-chromosome silencing in the female (i.e., only one X chromosome can be active at a time, so the other must be inactivated). More information has come to light about this lncRNA's structure and function. A new paper in the Proceedings of the National Academy of Sciences (PNAS) says this about the functional existence of Xist:
Long noncoding RNAs (lncRNAs) are important regulators of gene expression, but their structural features are largely unknown. We used structure-selective chemical probing to examine the structure of the Xist lncRNA in living cells and found that the RNA adopts well-defined and complex structures throughout its entire 18-kb length. By looking for changes in reactivity induced by the cellular environment, we were able to identify numerous previously unknown hubs of protein interaction. We also found that the Xist structure governs specific protein interactions in multiple distinct ways. Our results provide a detailed structural context for Xist function and lay a foundation for understanding structure-function relationships in all lncRNAs.
The current study, therefore, is another "tip of the iceberg" case that has implications for all lncRNAs. In this case, the researchers from University of North Carolina at Chapel Hill identified "complex well-defined secondary structure domains" in this 18,000-base RNA molecule that are related to specific functions.
The Xist RNA structure modulates protein interactions in cells via multiple mechanisms. For example, repeat-containing elements adopt accessible and dynamic structures that function as landing pads for protein cofactors. Structured RNA motifs create interaction domains for specific proteins and also sequester other motifs, such that only a subset of potential binding sites forms stable interactions. This work creates a broad quantitative framework for understanding structure-function interrelationships for Xist and other lncRNAs in cells.
A landing pad has a function, does it not? Think of an airport's landing strip with all the repeating lines down the center. Those repeats have a purpose, just as they do in Xist. Protein cofactors look for them to land on. Other proteins look for spots to take action, like markings on the stage floor for actors.
This RNA, once considered junk because it doesn't code for protein, has been elevated to a regulator of multiple important functions. Its shape tells other proteins where to land, where to interact, and what places to avoid. That shape is determined by the non-coding DNA that confers precise structures to the lncRNA. "Fully one-half of the Xist lncRNA forms well-defined structure motifs," the authors say. Anybody want to bet the other half will prove just as vital?
The authors feel their findings create a treasure hunt for further investigation into functions in the structure of lncRNAs. Or, to borrow another metaphor of theirs, it's time to listen to what the orchestra is playing.
The structured and unstructured domains identified here define maps that are expected to be invaluable in guiding investigations into the mechanisms by which Xist elements contribute to X chromosome inactivation. Xist and other lncRNA transcripts may span kilobases to coordinate long-range protein and domain interactions (Figs. 3 and 4) that ultimately enable orchestration of epigenetic regulation on the kilobase to megabase scales. Many lncRNAs are likely to share features identified here for Xist, including densely arrayed secondary structural features, multiple distinctive modes of protein interaction, and the ability to serve as multidomain organizers of cellular function.
Yes, there's function in the junk-tion, and it's music to our ears.
