Sunday, May 23, 2021

Noncoding “Junk” DNA Is Important for Limb Formation


Noncoding “Junk” DNA Is Important for Limb Formation
Casey Luskin

Image credit: Schäferle via Pixabay.

A 2021 article in Nature, “Non-coding deletions identify Maenli lncRNA as a limb-specific En1 regulator,” reports important new functions for non-coding or “junk” DNA that underlie limb formation. Before we get to the paper itself, consider a description of it on the Proceedings of the National Academy of Sciences “Journal Club” blog. The latter describes the research in terms that sound like they could have come directly from an intelligent design source: 

Genes that code for proteins make up only about 2% of the human genome. Many researchers once dismissed the other 98% of the genome as “junk DNA,” but geneticists now know these noncoding regions help to regulate the activity of the 20,000 or so protein-coding genes identified.

A new study in Nature underscores just how important noncoding DNA can be for human development. The authors show that deletions in a noncoding region of DNA on chromosome 2 cause severe congenital limb abnormalities. This is the first time a human disease has been definitively linked to mutations in noncoding DNA, says lead author Stefan Mundlos, head of the development and disease research group at the Max Planck Institute for Molecular Genetics in Berlin, Germany.

“Severe Congenital Limb Malformation” 

The technical paper in Nature describes the research. The investigators examined the chromosomes of people who had naturally occurring limb malformation, and found that these people had deletions of DNA encoding long non-coding RNA sequences (lncRNAs) from human chromosome 2. They deleted corresponding DNA sequences in mice and found similar “severe congenital limb malformation,” suggesting these lncRNA sequences are functionally important:

Here we show that genetic ablation of a lncRNA locus on human chromosome 2 causes a severe congenital limb malformation. We identified homozygous 27–63-kilobase deletions located 300 kilobases upstream of the engrailed-1 gene (EN1) in patients with a complex limb malformation featuring mesomelic shortening, syndactyly and ventral nails (dorsal dimelia). Re-engineering of the human deletions in mice resulted in a complete loss of En1expression in the limb and a double dorsal-limb phenotype that recapitulates the human disease phenotype. Genome-wide transcriptome analysis in the developing mouse limb revealed a four-exon-long non-coding transcript within the deleted region, which we named Maenli. Functional dissection of the Maenli locus showed that its transcriptional activity is required for limb-specific En1 activation in cis, thereby fine-tuning the gene-regulatory networks controlling dorso-ventral polarity in the developing limb bud. 

In the discussion, the article explains how important it is that we seek to understand the key functions of non-coding DNA sequences that encode lncRNAs:

In the era of whole-genome sequencing, the findings described here underscore the need for a systematic annotation and functional characterization of lncRNA loci to interpret and classify non-coding genetic variants. They highlight the importance of elucidating the complex diversity of lncRNA modes of action to assess their role in organ development and disease.

Over 130,000 Functional “Junk DNA” Elements!

So just how are we progressing in the task of determining the functions of non-coding DNA elements? Some defenders of evolutionary orthodoxy would have us believe that we’ve only found a handful of non-coding DNA sequences that have function — exceptions to the rule that non-coding DNA is usually useless junk. Another 2021 article in Nature shows why it’s no longer tenable for evolutionists to hide behind such an argument from ignorance. The article explains that over 130,000 functional “genomic elements, previously called junk DNA” have now been discovered, highlighting how important these “junk” segments have turned out to be:

[I]t is now appreciated that the majority of functional sequences in the human genome do not encode proteins. Rather, elements such as long non-coding RNAs, promoters, enhancers and countless gene-regulatory motifs work together to bring the genome to life. Variation in these regions does not alter proteins, but it can perturb the networks governing protein expression With the HGP draft in hand, the discovery of non-protein-coding elements exploded. So far, that growth has outstripped the discovery of protein-coding genes by a factor of five, and shows no signs of slowing. Likewise, the number of publications about such elements also grew in the period covered by our data set. For example, there are thousands of papers on non-coding RNAs, which regulate gene expression.

The article also observes that prior to the Human Genome Project, which was completed in 2003, there was “great debate” over whether it was “worth mapping the vast non-coding regions of genome that were called junk DNA, or the dark matter of the genome.” Under a paradigm informed by intelligent design, debates over whether to investigate junk DNA would have ended much sooner with an emphatic Yes!, furthering our knowledge of genetics and medicine. How much sooner would these 130,000+ “genomic elements, previously called junk DNA” have been uncovered if an ID paradigm had been governing biology research?