"Science" cover is heavy!

The human genome is often compared to a "book from the sky" for writing life.

At the beginning of the 21st century, the first draft of the human genome sequence was published, although incomplete, it has had a profound impact in the biomedical field, guiding the development of clinical research, drug development and medical practice

Twenty-one years later, the field of human genome sequencing has ushered in a new milestone: a more complete, gap-free human reference genome

This week, in six papers simultaneously online in the journal Science, an international research team called the Telomere-to-Telomere Consortium (T2T) announced the completion of the latest human reference genome (named T2T-CHM13), Includes seamless assembly of all 22 autosomes and X chromosomes

▲ "Science" magazine introduced the new results of human genome sequencing in the form of cover reports and special features (Image source: "Science" magazine official website)

Fill in the last 8% of the gaps

Due to the limitations of sequencing technology at the time, there were many gaps in the first draft of the human genome sequence

To fill the final void, nearly 100 scientists from dozens of research institutions formed a large team called the "T2T Consortium," or sequencing each chromosome from telomere at one end to telomere at the other

▲Compared with the previous human reference genome (GRCh38), this new version T2T-CHM13 fills in all the original gaps.

When reading a genome, scientists first cut all the DNA into fragments hundreds to thousands of letters long, the letters in each fragment are read by a sequencing machine, and then the scientists try to assemble the fragments in the correct order, like playing a Super complex puzzle

A big challenge in this process is that certain regions of the genome consist of large stretches of repeating letters, like pieces of a puzzle consisting of pieces that look the same, and these regions tend to have important biological features, and in some cases It is also associated with human disease

The research team found a cell line with only a single genome to eliminate the aforementioned problem of allelic diversity

The key progress in overcoming the difficulties is also inseparable from a major leap in sequencing technology

Unlock the most complex areas

About 90% of the new sequences unlocked this time come from the centromere of chromosomes

After T2T provided the complete sequence, humans had the first opportunity to understand the role of the centromere and its surrounding sequences

According to their analysis, there are various sequence stacking phenomena at the centromere and nearby regions, usually a new sequence overlaying an old sequence

▲The centromere is a region containing highly repetitive DNA sequences, and comparing these sequences revealed where mutations accumulated over millions of years, reflecting the relative age of each repeat (Image source: Reference [4]; Credit : Nicolas Altemose, UC Berkeley)

The old sequence will have some random mutations and deletions, indicating that this region has been deprecated; the new sequence has fewer mutations and methylation, indicating that it is being used

The repeat sequences of centromeres also vary from person to person

▲ New research reveals the evolutionary mechanism of human centromere genome sequence (Image source: Reference [4])

Finally, the fully sequenced region is obtained

In a series of results published this time, the researchers focused on analyzing the important role of repetitive segments in the genome in human evolution, the formation of genetic diversity and disease
.

A segmental duplication is a large segment of sequence that occurs repeatedly in the genome and has a sequence similarity of more than 90%
.
In the process of evolution both within and between species, most genetic variation occurs in the repetitive segment region, which is the key to the generation of new genes and adaptive changes in new gene functions
.
But because of the complexity of the structure, this is also the last region of the human genome to be fully sequenced
.

▲ More complete human genome sequencing results deepen our understanding of repetitive fragments (Image source: Reference [3])

Now, based on the latest complete human genome sequencing results, scientists are finally able to take a more comprehensive look at the human repeats
.
In such regions, scientists have identified 182 entirely new protein-coding genes that help us understand a range of important evolutionary and medical puzzles
.

For example, comparing human and other primate sequencing results, the study found the gene TBC1D3 associated with the expansion of the human prefrontal cortex, which will help to reconstruct the history of ancient human evolution
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Among different human individuals, the number of LPA genes encoding lipoproteins in the repeat region is highly correlated with the risk of cardiovascular disease.
.
.

Based on this study, we can fully understand the organization, expression and regulation of repeats, and improve gene annotation and genotyping
.

▲Detailed description of the transcription and methylation status of repetitive sequences in the human genome, laying the foundation for functional studies (Image source: Reference [6])

In another study, a team led by University of Connecticut Professor Rachel O'Neill revealed the transcriptional and epigenetic status of repeats
.
Repeated sequences contain mobile genetic elements that can move to other regions of the genome
.
The study pointed out that the genes contained in some repeated fragments can explain the genetic diversity of humans to a large extent
.

In addition to revealing the impact of specific repeats in humans from a genomic perspective, this study also analyzes the transcriptional landscape of the repeats locally (eg, in the centromere), mapping the methylation landscape
.
These results will help us understand the role of transcription in genome stability as well as the mechanism of chromosome segregation
.

References:

[1] Sergey Nurk et al.
, (2022) The complete sequence of a human genome.
Science.
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[2] Sergey Aganezov et al.
, (2022) A complete reference genome improves analysis of human genetic variation.
Science DOI: 10.
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[3] Mitchell R.
Vollger et al.
, (2022) Segmental duplications and their variation in a complete human genome.
Science https://doi.
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[4] Complete genomic and epigenetic maps of human centromeres.
Science(2022), DOI: 0.
1126/science.
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[5] A.
Gershman et al.
, Epigenetic patterns in a complete human genome.
Science 376, eabj5089 (2022).
DOI: 10.
1126/science.
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[6] SJ Hoyt et al.
, (2022) From telomere to telomere: The transcriptional and epigenetic state of human repeat elements Science DOI: 10.
1126/science.
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[7] Complete human genome deciphered for the first time.
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