Cell‐free fetal DNA coming in all sizes and shapes

Cell‐free fetal DNA analysis has an established role in prenatal assessments. It serves as a source of fetal genetic material that is accessible non‐invasively from maternal blood. Through the years, evidence has accumulated to show that cell‐free fetal DNA molecules are derived from placental tissues, are mainly of short DNA fragments and have rapid post‐delivery clearance profiles. But questions regarding how they come to being short molecules from placental cells and in which physical forms do they exist remained largely unanswered until recently. We now know that the distributions of ending sites of cell‐free DNA molecules are non‐random across the genome and bear correlations with the chromatin structures of cells from which they have originated. Such an insight offers ways to deduce the tissue‐of‐origin of these molecules. Besides, the physical nature and sequence characteristics of the ends of each cell‐free DNA molecule provide tell‐tale signs of how the DNA fragmentation processes are orchestrated by nuclease enzymes. These realizations offered opportunities to develop methods for enriching cell‐free fetal DNA to facilitate non‐invasive prenatal diagnostics. Here we aimed to collate what is known about the biological and physical characteristics of cell‐free fetal DNA into one article and explain the implications of these observations.