New Insights Into The Evolution Of The Human Genome

Which came first, the chicken genome or the egg genome?

Finding: The answers provide the first evolutionary history of the duplications in the human genome that are partly responsible for both disease and recent genetic innovations.

This work marks a significant step toward a better understanding of what genomic changes paved the way for modern humans, when these duplications occurred and what the associated costs are -- in terms of susceptibility to disease-causing genetic mutations.

Researchers have answered a similar vexing genomic question: Which of the thousands of long stretches of repeated DNA in the human genome came first? And which are the duplicates?

Genomes have an ability to copy a long stretch of DNA from one chromosome and insert it into another region of the genome. Segmental duplications hold many evolutionary secrets and uncovering them is a difficult biological and computational challenge with implications for both medicine and our understanding of evolution.

Evolutionary History
Researchers have created the first evolutionary history of the duplications in the human genome that are partly responsible for both disease and recent genetic innovations. This marks an important step toward a better understanding of what genomic changes paved the way for modern humans, when these duplications occurred and what the associated costs are - in terms of susceptibility to disease-causing genetic mutations.

In the past, the highly complex patterns of DNA duplication -- including duplications within duplications -- have prevented the construction of an evolutionary history of these long DNA duplications. To crack the duplication code and determine which of the DNA segments are originals (ancestral duplications) and which are copies (derivative duplications), the researchers looked to both algorithmic biology and comparative genomics.

Identifying the original duplications is a prerequisite to understanding what makes the human genome unstable. Researchers modified an algorithmic genome assembly technique in order to deconstruct the sequence of repeated stretches of DNA and identify the original sequences. The belief is that perhaps there may be something special about the originals, some clue or insight into what causes this colonization of the human genome.

This is the first time that we have a global view of the evolutionary origin of some of the most complicated regions of the human genome. The researchers tracked down the ancestral origin of more than two thirds of these long DNA duplications.

Special Findings:
First, researchers suggest that specific regions of the human genome experienced elevated rates of duplication activity at different times in our recent genomic history. This contrasts with most models of genomic duplication which suggest a continuous model for recent duplications. Second, a large fraction of the recent duplication architecture centers around a rather small subset of "core duplicons" -- short segments of DNA that come together to form segmental duplications. These cores are focal points of human gene/transcript innovations.

Not all of the duplications in the human genome are created equal. Some of them -- the core duplicons -- appear to be responsible for recent genetic innovations the in human genome. Researchers uncovered 14 such core duplicons.

In 4 of the 14 cases, there is compelling evidence that genes embedded within the cores are associated with novel human gene innovations. In two cases the core duplicon has been part of novel fusion genes whose functions appear to be radically different from their antecedents.

Results suggest that the high rate of disease caused by these duplications in the normal population may be offset by the emergence of newly minted human/great-ape specific genes embedded within the duplications. The next challenge will be determining the function of these novel genes.

Mathematical Algorithms and Biological construction
Research applied their expertise in assembling genomes from millions of small fragments -- a problem that is not unlike the "mosaic decomposition" problem in analyzing duplications that the team faced.

Over the years researchers applied the 250-year old algorithmic idea first proposed by 18th century mathematician Leonhard Euler (of the fame of pi) to a variety of problems and demonstrated that it works equally well for a set of seemingly unrelated biological problems including DNA fragment assembly, reconstructing snake venoms, and now dissecting the mosaic structure of segmental duplications.

DNA Replication Behavior- from Low to High

DNA replication is considered the heart of the DNA process. Recent findings by scientists at the Genome Institute of Singapore (GIS) may be paving the way for more efficient analyses and tests related to the replication of cells, and ultimately, to the better understanding of human biology, such as in stem cell research.

Where does duplication occur?
Faithful duplication of the genome ensures that daughter cells inherit a complete set of genetic materials identical to parent cells. This duplication occurs in the section of the cell cycle known as the S-phase. Extensive research on the budding yeast revealed that the replication process is started at hundreds of origins in the S-phase.

Is the replication process efficient?
Many previous studies focused on the replication timing and initiation sites, but not on the efficiency. So it was believed that the replication efficiency decreased as the S-phase progressed.
But now they know better. In a recently published paper scientists described how they were able to determine the replication timing and efficiency at the various loci in the genome. Now replication efficiency is low at the beginning of the S-phase, but the efficiency increased at the later stage of this phase.

Genetic evidence for evolution

If there is evolution, is there any evidence for it at the genetic level?

The answer is yes. Scientists who have been studying genetic changes occurring in the human genome over the last 15,000 to 100,000 years, have found that over this relatively short period of time the human genome has changed by as much as 10 percent.

Evidence withing the Human Genome
A scientific study identifies small, gradual changes (microevolution) that demonstrate species divergence from a common ancestor millions of years ago (macroevolution). The study makes human-to-human comparisons throughout the complete human genome instead of comparing a human to mice or chimpanzees. By this procedure humans can be seen changing over time, due to our ancestors being exposed to – among other selective pressures – different climates as they spread across the globe.

Evidence for Change
Early humans had problems digesting lactose after the age of one. Lactose is an enzyme found in milk. Befor the domestication of animals (about 20,000 years ago) humans could not digest milk after infancy. But some time after humans began migrating and domesticating animals, humans began to develop a gene that allowed us to tolerate consuming milk into adulthood. In other words as humans have populated the world, there has been strong selective pressure at the genetic level for mutations that allow digestion of a new food source or tolerate infection by a pathogen that the population may not have faced in a previous environment.

Shrinking Genomes

Scientists generally believe that insertions of retroelements, or"jumping genes," once established in a population, are irreversible and are maintained throughout evolution. This unidirectional theory of retroelement evolution, which calls for ever-expanding genome size, is challenged by work that appears in the September issue of Genome Research.

Deletion of Genome elements from Rhesus to Humans
Researchers performed a whole-genome comparison of the human, chimpanzee, and Rhesus monkey sequences, and they identified 37 instances where a retroelement was present in Rhesus (a more primitive primate species) but absent in either humans or chimpanzees. This indicated that these retroelements had been deleted during the evolution of the more recent primate species.

Mediation by short identical sequences
Intriguingly, the scientists further demonstrated that these deletions were mediated by short identical sequences that flank the retroelements. They extended the study to random, non-retroelement sequences and showed that deletions caused by short identical DNAsequences were a widespread genomic phenomenon. In fact, thousands of insertion-deletion sequence differences between the human and chimpanzee genomes were likely mediated by short identical sequences.

The work strongly suggests an important role for short, non-adjacent, identical segments of DNA in genomic deletions and it lends insight into deletion mechanisms that help to counterbalance genome expansion in primates.

Conclusion: Genes don't get bigger with more complex species, they get smaller.

Molecular evolution

Molecular evolution is the process of evolution at the scale of DNA, RNA, and proteins.

Some of the key topics that spurred development of the field have been

• the evolution of enzyme function,
• the use of nucleic acid divergence as a "molecular clock" to study species divergence,
• and the origin of non-functional or junk DNA.

Recent advances in genomics, including whole-genome sequencing, high-throughput protein characterization, and bioinformatics have led to a dramatic increase in studies on the topic. In the 2000s, some of the active topics have been the role of gene duplication in the emergence of novel gene function, the extent of adaptive molecular evolution versus neutral drift, and the identification of molecular changes responsible for various human characteristics especially those pertaining to infection, disease, and cognition.

The Chloroplast Genome

The genome of the chloroplasts found in Marchantia polymorpha contains 121,024 base pairs in a closed circle.

A chloroplast is the organelle that carries out photosynthesis and starch grain formation. It is a chlorophyll-containing organelle in plants that is the site of photosynthesis.

These make up some 128 genes which include:

• duplicate genes encoding each of the four subunits (23S, 16S, 4.5S, and 5S) of the ribosomal RNA (rRNA) used by the chloroplast
• 37 genes encoding all the transfer RNA (tRNA) molecules used for translation within the chloroplast.

Some of these are represented in the figure by black bars.
4 genes encoding some of the subunits of the RNA polymerase used for transcription within the chloroplast (the blue ones)
a gene encoding the large subunit of the enzyme ribulose bisphosphate carboxylase oxygenase (RUBISCO)

9 genes for components of photosystems I and II
6 genes encoding parts of the chloroplast ATP synthase
genes for 19 of the ~60 proteins used to construct the chloroplast ribosome

The Mitochondrial Genome

What does the genome of human mitochondria look like?

It contains 16,569 base pairs of DNA organized in a closed circle.

These encode:

• 2 ribosomal RNA (rRNA) molecules
• 22 transfer RNA (tRNA) molecules (shown in the figure as yellow bars; two of them labeled)
• 13 polypeptides.

The 13 polypeptides participate in building several protein complexes embedded in the inner mitochondrial membrane.

• 7 subunits that make up the mitochondrial NADH dehydrogenase
• 3 subunits of cytochrome c oxidase
• 2 subunits of ATP synthase cytochrome b

All these gene products are used within the mitochondrion, but the mitochondrion also needs proteins encoded by nuclear genes. These proteins are synthesized in the cytosol and then imported into the mitochondrion.

Why are there variations in Genome Size?

The genome size varies considerably from one species to another. The enormity of the c. 40 000-fold range in genome size have intrigued scientists for over half a century. Scientists have asked how and why genomes vary so extensively and whether it matters. But recent findings have extended a paleogenomics dimension to these questions. By using the size of fossil dinosaur bone cells as proxies for genome size, they have attempted to trace the evolution of genome size in reptiles over 200 million years. By analyzing currently available sequence data from a range of reptiles and birds, they have aimed to shed light on the genomic makeup of dinosaur genomes.

Size doesn't matter
Back in the later 1940's estimates of genome size were made, but as data increased, it soon became clear that there was a huge disparity between organismal complexity and genome size. In other words, a complex animal does not guarantee a large genome. In fact, the lowly liverwort has 18 times as much DNA as we have, and the slimy, dull salamander known as Amphiuma has 26 times our complement of DNA'.

Where does Genome size diversity come from?
Since then, there has been much progress in understanding the molecular basis behind how genomes vary so extensively in size. It is now widely accepted that genome size diversity arises from differences in the amount of non-coding repetitive DNA (e.g. pseudogenes, retrotransposons, transposons satellite repeats, and so on.).

Where does the size of the Genome come from?
The actual genome size of an organism is determined by the differential activity of mechanisms generating increases such as retrotransposon amplification, polyploidy, segmental duplications or generating decreases like illegitimate and unequal recombination, or differences in double-strand break repair in the DNA amount.

Genetic variation and Genetic stability

Scientists from the Max-Plank institute and from the Salk Institute and the university of Chicago have identified which genes are prone to variation and which are stable and do not have modification. They have developed a method to sift out whole genomes for all the environmental fixes and addendums accumulated over time. What the scientists are after is the regions that are currently targeted by natural selection or have been so during the evolutionary past.

This is an exciting prospect because it lends itself to a further accumulation of evidence about how evolution works. The entire genome isn't affected, only parts of it. Scientists studying the plant the mustard weed Arabidopsis thaliana have been able to identify genetic variations in 23 strains.

Why study arabidopsis?
About 10 years ago Arabidopsis was adopted by plant scientists as an easily manipulated model for other plants because it is simple to grow in the laboratory, has a short life cycle and a small genome. Arabidopsis only has about 120 million base pairs of DNA. Compared to corn, which might have as many as 2.5 billion base pairs of DNA and the human genome with roughly 3 billion pairs, one can study it more easily.

Effects on genes
Plants are under constant threat from heat, cold, high acidity or salinity, or pathogens such as viruses and leaf-munching insects. So how do plants survive? Plants mobilize physiological and biochemical defenses for their survival. Scientists expected certain classes of genes to be highly variable due to natural selection in different environments. And now two different studies revealed precisely which gene family members indeed were shaped by evolution. In general, genes that don't change over time are under strong negative selection because they perform important housekeeping functions, while genes that vary widely such as disease resistance genes are under strong positive selection.

DNA and Genome transfer from one Bacterial Species to Another

Scientists are now able to take the genetic material from one bacterial species and transfer it to another, basically swapping their Genomes. The implications for synthetic custom - built bugs is astonishing.

The experiment marks the attempt to re-engineer a living cell with a view to one day developing micro-organisms that were different than how nature designed them. Some could be used for biofuels, cleaning up toxic waste, sequestering carbon or other applications.

Transplanting the entire genome from one species to another and having it work is the equivalent of taking a MacIntosh computer and making it a PC by inserting a new piece of software.

For the first time it is possible to insert an intact genome into a host organism and have that second organism express the original-foreign DNA.

But what is next? To create a synthetic genome and then transplant that one into a host organism.

From an evolutionary perspective, it would indicate that if man could do something like this, it would be possible for it to also occur in nature. In other words, the variation that we see in nature, may have come about with the co-mingling of genomes from different species.

DNA Polymerase and Genome stability

Why are genomes unstable? What factors in the environment can cause a DNA strand to be replicated? Well the answer comes from the fact that an enzyme called DNA polymerase epsilon plays a significant role in replicating DNA in higher organisms such as yeast and perhaps even humans.

An enzyme is a protein that acts as a catalyst for chemical reactions. A protein is a molecule made up of a sequence of amino acids. They are the unit molecular building blocks of proteins. They occur in a certain sequence. And there are 20 main amino acids in the proteins of living things, and the properties of a protein are determined by its particular amino acid sequence.
In 1953 Watson and Crick first described the structure of DNA, they also pointed out that the two DNA strands, referred to as leading and lagging, pair with each other to form the now familiar double helix.

Researchers at the Umeå University in Sweden found that in baker's yeast, the primary role in replicating the leading strand of DNA was the enzyme called DNA polymerase epsilon. This enzyme was found to be a key determinant providing genome stability and it also is responsible for cellular responses to DNA damage resulting from exposures to environmental stress.

In the mid 50's researchers discovered the first enzymes capable of replicating DNA. This is an important process required to make new genomes for cell division. So the enzymes, called DNA polymerases, were shown to copy the two DNA strands in only one of two possible directions. One strand of the double helix must be replicated first by a dedicated leading strand polymerase, then it was followed by replication from the lagging strand by a different polymerase.

In lower organisms like the E. coli bacteria one DNA polymerase can accomplish both tasks. But with humans and related higher organisms, such as baker's yeast, the DNA polymerase function is more complicated. Some discoveries, which emerged from the human genome project, indicate that the human genome encodes at least 15 DNA polymerases that can copy DNA. Their tasks appear to be different. Some are thought to perform genomic replication, but others operate under special circumstances, such as to repair DNA damage resulting from environmental exposures.