Tag: encode

Genome Code Builds the Case for Creation

By Fazale Rana – December 18, 2019

A few days ago, I was doing a bit of Christmas shopping for my grandkids and I happened across some really cool construction kits, designed to teach children engineering principles while encouraging imaginative play. For those of you who still have a kid or two on your Christmas list, here are some of the products that caught my eye:

These building block sets are a far cry from the simple Lego kits I played with as a kid.

As cool as these construction toys may be, they don’t come close to the sophisticated construction kit cells use to build the higher-order structures of chromosomes. This point is powerfully illustrated by the insights of Italian investigator Giorgio Bernardi. Over the course of the last several years, Bernardi’s research teams have uncovered design principles that account for chromosome structure, a set of rules that he refers to as the genome code.1

To appreciate these principles and their theological implications, a little background information is in order. (For those readers familiar with chromosome structure, skip ahead to The Genome Code.)

Chromosomes

DNA and proteins interact to make chromosomes. Each chromosome consists of a single DNA molecule wrapped around a series of globular protein complexes. These complexes repeat to form a supramolecular structure resembling a string of beads. Biochemists refer to the “beads” as nucleosomes.

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Figure 1: Nucleosome Structure. Image credit: Shutterstock

The chain of nucleosomes further coils to form a structure called a solenoid. In turn, the solenoid condenses to form higher-order structures that constitute the chromosome.

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Figure 2: Chromosome Structure Image credit: Shutterstock

Between cell division events (called the interphase of the cell cycle), the chromosome exists in an extended diffuse form that is not readily detectable when viewed with a microscope. Just prior to and during cell division, the chromosome condenses to form its readily recognizable compact structures.

Biologists have discovered that there are two distinct regions—labeled euchromatin and heterochromatin for chromosomes in the diffuse state. Euchromatin is resistant to staining with dyes that help researchers view it with a microscope. On the other hand, heterochromatin stains readily. Biologists believe that heterochromatin is more tightly packed (and, hence, more readily stained) than euchromatin. They have also learned that heterochromatin associates with the nuclear envelope.

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Figure 3: Structure of the Nucleus Showing the Distribution of Euchromatin and Heterochromatin. Image credit: Wikipedia

The Genome Code

Historically, biologists have viewed chromosomes as consisting of compositionally distinct units called isochores. In vertebrate genomes, five isochores exist (L1, L2, H1, H2, and H3). The isochores differ in the composition of guanine- and cytosine-containing deoxyribonucleotides (two of the four building blocks of DNA). The GC composition increases from L1 to H3. Gene density also increases, with the H3 isochore possessing the greatest number of genes. On the other hand, the size of DNA pieces of compositional homogeneity decreases from L1 to H3.

Bernardi and his collaborators have developed evidence that the isochores reflect a fundamental unit of chromosome organization. The H isochores correspond to GC-rich euchromatin (containing most of the genes) and the L isochores correspond to GC-poor heterochromatin (characterized by gene deserts).

Bernardi’s research teams have demonstrated that the two groups of isochores are characterized by different distributions of DNA sequence elements. GC-poor isochores contain a disproportionately high level of oligo A sequences while GC-rich isochores harbor a disproportionately high level of oligo G sequences. These two different types of DNA sequence elements form stiff structures that mold the overall three-dimensional architecture of chromosomes. For example, oligo A sequences introduce curvature to the DNA double helix. This topology allows the double helix to wrap around the protein core that forms nucleosomes. The oligo G sequence elements adopt a topology that weakens binding to the proteins that form the nucleosome core. As Bernardi points out, “There is a fundamental link between DNA structure and chromatin structure, the genomic code.”2

In other words, the genomic code refers to a set of DNA sequence elements that:

  1. Directly encodes and molds chromosome structure (while defining nucleosome binding),
  2. Is pervasive throughout the genome, and
  3. Overlaps the genetic code by constraining sequence composition and gene structure.

Because of the existence of the genomic code, variations in DNA sequence caused by mutations will alter the structure of chromosomes and lead to deleterious effects.

The bottomline: Most of the genomic sequence plays a role in establishing the higher-order structures necessary for chromosome formation.

Genomic Code Challenges the Junk DNA Concept

According to Bernardi, the discovery of the genomic code explains the high levels of noncoding DNA sequences in genomes. Many people view such sequences as vestiges of an evolutionary history. Because of the existence and importance of the genomic code, the vast proportion of noncoding DNA found in vertebrate genomes must be viewed as functionally vital. According to Bernardi:

Ohno, mostly focusing on pseudo-genes, proposed that non-coding DNA was “junk DNA.” Doolittle and Sapienza and Orgel and Crick suggested the idea of “selfish DNA,” mainly involving transposons visualized as molecular parasites rather than having an adaptive function for their hosts. In contrast, the ENCODE project claimed that the majority (~80%) of the genome participated “in at least one biochemical RNA-and/or chromatin-associated event in at least one cell type.”…At first sight, the pervasive involvement of isochores in the formation of chromatin domains and spatial compartments seems to leave little or no room for “junk” or “selfish” DNA.3

The ENCODE Project

Over the last decade or so, ENCODE Project scientists have been seeking to identify the functional DNA sequence elements in the human genome. The most important landmark for the project came in the fall of 2012 when the ENCODE Project reported phase II results. (Currently, ENCODE is in phase IV.) To the surprise of many, the project reported that around 80 percent of the human genome displays biochemical activity—hence, function—with many scientists anticipating that that percentage would increase as phases III and IV moved toward completion.

The ENCODE results have generated quite a bit of controversy, to say the least. Some researchers accept the ENCODE conclusions. Others vehemently argue that the conclusions fly in the face of the evolutionary paradigm and, therefore, can’t be valid. Of course, if the ENCODE Project conclusions are correct, then it becomes a boon for creationists and intelligent design advocates.

One of the most prominent complaints about the ENCODE conclusions relates to the way the consortium determined biochemical function. Critics argue that ENCODE scientists conflated biochemical activity with function. These critics assert that, at most, about ten percent of the human genome is truly functional, with the remainder of the activity reflecting biochemical noise and experimental artifacts.

However, as Bernardi points out, his work (independent of the ENCODE Project) affirms the project’s conclusions. In this case, the so-called junk DNA plays a critical role in molding the structures of chromosomes and must be considered functional.

Function for “Junk DNA”

Bernardi’s work is not the first to recognize pervasive function of noncoding DNA. Other researchers have identified other functional attributes of noncoding DNA. To date, researchers have identified at least five distinct functional roles that noncoding DNA plays in genomes.

  1. Helps in gene regulation
  2. Functions as a mutational buffer
  3. Forms a nucleoskeleton
  4. Serves as an attachment site for mitotic apparatus
  5. Dictates three-dimensional architecture of chromosomes

A New View of Genomes

These types of insights are forcing us to radically rethink our view of the human genome. It appears that genomes are incredibly complex, sophisticated biochemical systems and most of the genes serve useful and necessary functions.

We have come a long way from the early days of the human genome project. Just 15 years ago, many scientists estimated that around 95 percent of the human genome consists of junk. That acknowledgment seemingly provided compelling evidence that humans must be the product of an evolutionary history. Today, the evidence suggests that the more we learn about the structure and function of genomes, the more elegant and sophisticated they appear to be. It is quite possible that most of the human genome is functional.

For creationists and intelligent design proponents, this changing view of the human genome provides reasons to think that it is the handiwork of our Creator. A skeptic might wonder why a Creator would make genomes littered with so much junk. But if a vast proportion of genomes consists of functional sequences, then this challenge no longer carries weight and it becomes more and more reasonable to interpret genomes from within a creation model/intelligent design framework.

What a Christmas gift!

Resources

Junk DNA Regulates Gene Expression

Junk DNA Serves as a Mutational Buffer

Junk DNA Serves a Nucleoskeletal Role

Junk DNA Plays a Role in Cell Division

ENCODE Project

Studies that Affirm the ENCODE Results

Endnotes
  1. Giorgio Bernardi, “The Genomic Code: A Pervasive Encoding/Molding of Chromatin Structures and a Solution of the ‘Non-Coding DNA’ Mystery,” BioEssays 41, no. 12 (November 8, 2019), doi:10.1002/bies.201900106.
  2. Bernardi, “The Genomic Code.”
  3. Bernardi, “The Genomic Code.”

Reprinted with permission by the author

Original article at:

https://reasons.org/explore/blogs/the-cells-design

Protein-Binding Sites ENCODEd into the Design of the Human Genome

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BY FAZALE RANA – MARCH 15, 2017

At last year’s AMP Conference, I delivered a talk titled: “How the Greatest Challenges Can Become the Greatest Opportunities for the Gospel.” I illustrated this point by describing three scientific concepts related to the origin of humanity that 20 years ago stood as insurmountable challenges to the traditional biblical view of human origins. But, thanks to scientific advances, these concepts have been replaced with new insights that turn these challenges into evidence for the Christian faith.

The Challenge of Junk DNA

One of the challenges I discussed centered on junk DNA—nonfunctional DNA littering the genomes of most organisms. Presumably, these nonfunctional DNA sequences arose through random biochemical, chemical, and physical events, with functional DNA converted into useless junk, in some instances. In fact, when the scientific community declared the human genome sequence completed in 2003, estimates at that time indicated that around 95 percent of the human genome consist of junk sequences.

Since I have been involved in apologetics (around 20 years), skeptics (and believers) have regarded the high percentages of junk DNA in genomes as a significant problem for intelligent design and creation models. Why would an all-powerful, all-knowing, and all-good God create organisms with so much junk in their genomes? The shared junk DNA sequences found among the genomes of humans and the great apes compounds this challenge. For many, these shared sequences serve as compelling evidence for common ancestry among humans and the other primates. Why would a Creator introduce nonfunctional DNA sequences into corresponding locations in genomes of humans and the great apes?

But what if the junk DNA sequences are functional? It would undermine the case for common descent, because these shared sequences could reasonably be interpreted as evidence for common design.

The ENCODE Project

In recent years, numerous discoveries indicate that virtually every class of junk DNA displays function, providing mounting support for a common-design interpretation of junk DNA. (For a summary, see the expanded and updated edition of Who Was Adam?) Perhaps the most significant advance toward that end came in the fall of 2012 with the publication of phase II results of the ENCODE project—a program carried out by a consortium of scientists with the goal of identifying the functional DNA sequence elements in the human genome.

To the surprise of many, the ENCODE project reported that around 80 percent of the human genome displays function, with the expectation that this percentage should increase with phase III of the project. Many of the newly recognized functional elements play a central role in regulating gene expression. Others serve critical roles in establishing and maintaining the three-dimensional hierarchical structure of chromosomes.

If valid, the ENCODE results would force a radical revision of the way scientists view the human genome. Instead of a wasteland littered with junk DNA sequences, the human genome (and the genome of other organisms) would have to be viewed as replete with functional elements, pointing to a system far more complex and sophisticated than ever imagined—befitting a Creator’s handiwork. (See the articles listed in the Resources section below for more details.)

ENCODE Skeptics

Within hours of the publication of the phase II results, evolutionary biologists condemned the ENCODE project, citing a number of technical issues with the way the study was designed and the way the results were interpreted. (For a response to these complaints go here, here, and here.)

These technical complaints continue today, igniting the junk DNA war between evolutionary biologists and genomics scientists. Though the concerns expressed by evolutionary biologists are technical, some scientists have suggested the real motivation behind the criticisms of the ENCODE project are philosophical—even theological—in nature. For example, molecular biologists John Mattick and Marcel Dinger write:

There may also be another factor motivating the Graur et al. and related articles (van Bakel et al. 2010; Scanlan 2012), which is suggested by the sources and selection of quotations used at the beginning of the article, as well as in the use of the phrase ‘evolution-free gospel’ in its title (Graur et al. 2013): the argument of a largely non-functional genome is invoked by some evolutionary theorists in the debate against the proposition of intelligent design of life on earth, particularly with respect to the origin of humanity. In essence, the argument posits that the presence of non-protein-coding or so-called ‘junk DNA’ that comprises >90% of the human genome is evidence for the accumulation of evolutionary debris by blind Darwinian evolution, and argues against intelligent design, as an intelligent designer would presumably not fill the human genetic instruction set with meaningless information (Dawkins 1986; Collins2006). This argument is threatened in the face of growing functional indices of noncoding regions of the genome, with the latter reciprocally used in support of the notion of intelligent design and to challenge the conception that natural selection accounts for the existence of complex organisms (Behe 2003; Wells 2011).1

Is DNA-Binding Activity Functional?

Even though there may be nonscientific reasons for the complaints leveled against the ENCODE project, it is important to address the technical concerns. One relates to how biochemical function was determined by the ENCODE project. Critics argued that ENCODE scientists conflated biochemical activity with function. As a case in point, three of the assays employed by the ENCODE consortium measure binding of proteins to the genome, with the assumption that binding of transcription factors and histones to DNA indicated a functional role for the target sequences. On the other hand, ENCODE skeptics argue that most of the measured protein binding to the genome was random.

Most DNA-binding proteins recognize and bind to short stretches of DNA (4 to 10 base pairs in length) comprised of highly specific nucleotide sequences. But given the massive size of the human genome (3.2 billion genetic letters), nonfunctional binding sites will randomly occur throughout the genome, for statistical reasons alone. To illustrate: Many DNA-binding proteins target roughly between 1 and 100 sites in the genome. Yet, the genome potentially harbors between 1 million and 1 billion binding sites. The hundreds of sites that are slight variants of the target sequence will have a strong affinity to the DNA-binding proteins, with thousands more having weaker affinities. Hence, the ENCODE critics maintain that much of the protein binding measured by the ENCODE team was random and nonfunctional. To put it differently, much of the protein binding measured in the ENCODE assays merely is a consequence of random biochemical activity.

Nonfunctional Protein Binding to DNA Is Rare

This challenge does have some merit. But, this criticism may not be valid. In an earlier response to this challenge, I acknowledged that some protein binding in genomes will be random and nonfunctional. Yet, based on my intuition as a biochemist, I argued that random binding of proteins throughout the genome would be disruptive to DNA metabolism, and, from an evolutionary perspective would have been eliminated by natural selection. (From an intelligent design/creation model vantage point, it is reasonable to expect that a Creator would design genomes with minimal nonfunctional protein-binding sites.)

As it happens, new work by researchers from NYU affirms my assessment.2 These investigators demonstrated that protein binding in genomes is not random but highly specific. As a corollary, the human genome (and genomes of other organisms) contains very few nonfunctional protein-binding sites.

To reach this conclusion, these researchers looked for nonfunctional protein-binding sites in the genomes of 75 organisms, representative of nearly every major biological group, and assessed the strength of their interaction with DNA-binding proteins. The researchers began their project by measuring the binding affinity for a sample of regulatory proteins (from humans, mice, fruit flies, and yeast) with every possible 8 base pair sequence combination (32,896). Based on the binding affinity data, the NYU scientists discovered that nonfunctional binding sites with a high affinity for DNA binding proteins occurred infrequently in genomes. To use scientific jargon to describe their findings: The researchers discovered a negative correlation between protein-binding affinity and the frequency of nonfunctional binding sites in genomes. Using statistical methods, they demonstrated that this pattern holds for all 75 genomes in their study.

They attempted to account for the frequency of nonfunctional binding sequences in genomes by modeling the evolutionary process, assuming neutral evolution in which random mutations accrue over time free from the influence of natural selection. They discovered that this modeling failed to account for the sequence distributions they observed in the genomes, concluding that natural selection must have weeded high affinity nonfunctional binding sites in genomes.

These results make sense. The NYU scientists point out that protein mis-binding would be catastrophic for two reasons: (1) it would interfere with several key processes, such as transcription, gene regulation, replication, and DNA repair (the interference effect); and (2) it would create inefficiencies by rendering DNA-binding proteins unavailable to bind at functional sites (the titration effect). Though these problems may be insignificant for a given DNA-binding protein, the cumulative effects would be devastating because there are 100 to 1,000 DNA-binding proteins per genome with 10 to 10,000 copies of each protein.

The Human Genome Is ENCODEd for Design

Though the NYU researchers conducted their work from an evolutionary perspective, their results also make sense from an intelligent design/creation model vantage point. If genome sequences are truly the product of a Creator’s handiwork, then it is reasonable to think that the sequences comprising genomes would be optimized—in this case, to minimize protein mis-binding. Though evolutionary biologists maintain that natural selection shaped genomes for optimal protein binding, as a creationist, it is my contention that the genomes were shaped by an intelligent Agent—a Creator.

These results also have important implications for how we interpret the results of the ENCODE project. Given that the NYU researchers discovered that high affinity nonfunctional binding sites rarely occur in genomes (and provided a rationale for why that is the case), it is difficult for critics of the ENCODE project to argue that transcription factor and histone binding assays were measuring mostly random binding. Considering this recent work, it makes most sense to interpret the protein-binding activity in the human genome as functionally significant, bolstering the original conclusion of the ENCODE project—namely, that most of the human genome consists of functional DNA sequence elements. It goes without saying: If the original conclusion of the ENCODE project stands, the best evidence for the evolutionary paradigm unravels.

Our understanding of genomes is in its infancy. Forced by their commitment to the evolutionary paradigm, many biologists see genomes as the cobbled-together product of an unguided evolutionary history. But as this recent study attests, the more we learn about the structure and function of genomes, the more elegant and sophisticated they appear to be. And the more reasons we have to believe that genomes are the handiwork of our Creator.

Resources

Endnotes

  1. John S. Mattick and Marcel E. Dinger, “The Extent of Functionality in the Human Genome,” The HUGO Journal 7 (July 2013): doi:10.1186/1877-6566-7-2.
  2. Long Qian and Edo Kussell, “Genome-Wide Motif Statistics Are Shaped by DNA Binding Proteins over Evolutionary Time Scales,” Physical Review X 6 (October–December 2016): id. 041009, doi:10.1103/PhysRevX.6.041009.
Reprinted with permission by the author
Original article at:
https://www.reasons.org/explore/blogs/the-cells-design/read/the-cells-design/2017/03/15/protein-binding-sites-encoded-into-the-design-of-the-human-genome